[No public or meaningful name is available]

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2019

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:

Short-term repeated dose toxicity provides robust data for quantitative inhalation risk assessment. The aim was to estimate the short-term repeated dose toxicity of target substance.

Estimation of the biological activity (short-term repeated dose toxicity)
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. Analogue (source compound) search based on selected criteria:
a. analogue dissociates similarly like the target compound (dissociation simulator)
b. analogue transforms similarly like the target compound (in vivo rat metabolism simulator)
c. analogue has the similar transformation products as the target compound (metabolism simulator, similarity >50%).
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 1
Toxicity prediction for the target substance:
The target chemical is classified as a “Aliphatic amines” according to structure-based profilers and does not have repeated-dose alerts responsible for the toxic effect based on the HESS profiler. No effect is expected.

3 dissociating products and 3 in vivo rat liver metabolites are produced after accounting for (a)biotic simulation (dissociation, rat in vivo metabolism). However, based on the fact that target compound undergoes dissociation reaction it is expected that this will be the one of first reactions to which target is exposed. Thus, the prediction is based on toxicological data of the source compound with similar dissociation products.
The target substance is an organometallic compound containing manganese (Mn) centres, glycine (Gly) and manganese (II) sulphate (MnSO4) ligands. The metallic centres of the substance are linked by oxygen coordination bonds of the Gly ligands.
This read-across is based on the hypothesis that source and target substances have similar toxicological properties due to their dissociation into basic products (Gly, H2SO4 and Mn(OH)2). Glycine is an amino acid, which is not considered as toxic compound. Manganese (II) sulphate (MnSO4) would have the same dissociation products (H2SO4 and Mn(OH)2). However, since there were no data available for the MnSO4, the prediction was performed basing on a transformation analogue search assuming at least 50% similarity between dissociation products of source and target substances (besides glycine). CuSO4 analogue has been found as the most similar chemical, therefore it was used as the source compound.
The short-term repeated dose toxicity for the source compound was performed according to:
Test guideline: OECD 412
Endpoint: NOAEL
Test organism: rat
Duration: 28 day
The read-across prediction of the short-term repeated dose toxicity for the target substance was performed based on the approach “one to one”.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

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 short-term repeated dose toxicity of the dehydrate manganese (II) glycine sulphate (VI), the read-across hypothesis considers that source and target compounds have the similar transformation products. Based on the Dice measure, the structural similarity between dissociation products of source and target substances was higher than 50%. CuSO4 analogue has been found as the most similar chemical, therefore it was used as the source compound.
Besides, the category consistency, the boundaries of the applicability domain are verified by the critical value of log KOW as well as chemical elements profile. In case of “one to one” approach, these criteria would be met only if source and target compounds are the same substance. Thus, information that “target chemical is out of domain” considering these criteria is not critical in this situation.
The structural similarity between the source (CuSO4) and the target compound (Mn(Gly)SO4) equals to 35.3% .

Test material

Test material information

Constituent 1

Reference substance name:

catena-((μ4-sulfato)-(μ2-glycinato)-manganese

Cas Number:

2087529-10-8

Molecular formula:

Mn(SO4)(C2H5NO2)

IUPAC Name:

catena-((μ4-sulfato)-(μ2-glycinato)-manganese

Test material form:

solid

Results and discussion

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

2 mg/m³ air

Basis for effect level:

other: not specific (QSAR)

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

The short-term repeated dose toxicity for the target substance is predicted at level NOAEL = 2.00 mg/m3 air

Executive summary:

The target compound undergoes an dissociation reaction into its basic products: Gly, H2SO4a nd Mn(OH)2. Due to the glycine is an amino acid which is not considered as toxic compound, the analogues search was performed assuming at least 50% of structural similarity between dissociation products of source and target substances. The toxicity prediction was performed based on the experimental data included in the OECD QSAR Toolbox. CuSO4 would have similar dissociation products (H2SO4 and Cu(OH)2) as well as the experimental data related to its short-term repeated dose toxicity was measured according to the recommended OECD

guideline. Prediction is based only on the CuSO4.