Butyl 3-mercaptopropionate

Endpoint summary

Description of key information

Based on read across from MMP, BuMP is considered toxic if swallowed (LD50 = 194 mg/kg bw), toxic by inhalation (4-h LC50, vapour = 2.11 mg/L), and harmful via dermal route (LD50 = 1905 mg/kg bw).

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)

Adequacy of study:

key study

Justification for type of information:

see category report attached as "full study report"

Reason / purpose for cross-reference:

read-across source

Species:

rat

Route of administration:

oral: gavage

Key result

Dose descriptor:

LD50

Effect level:

193.9 mg/kg bw

Based on:

other: read across from MMP

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

194 mg/kg bw

Quality of whole database:

read across from valid study with MMP

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

see category report attached as "full study report"

Reason / purpose for cross-reference:

read-across source

Principles of method if other than guideline:

read across from MMP using the OECD QSAR Toolbox 4.2

Species:

rat

Route of administration:

inhalation: vapour

Dose descriptor:

LC50

Effect level:

430 ppm

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

2.11 mg/L air (analytical)

Based on:

other: read across from MMP

95% CL:

>= 1.89 - <= 2.25

Exp. duration:

4 h

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Based on read-across from MMP, the 4-h Inhalation LC50 of BuMP as vapour is 2.11 mg/L. This read across is conservative due to the lower vapour pressure of BuMP.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

2.11 mg/m³

Quality of whole database:

read across from valid study with MMP

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

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

Remarks:

One-to-one read-across

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
A brief overview of the read-across study is reported below. Detailed information on the read-across justification is included in the read-across study report available in the "Attached justification" field. Please also refer to this report for the list of tools used in the assessment.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH

The present read-across study falls within the RAAF scenario 2, i.e. one-to-one analogue approach based on the hypothesis that different compounds are supposed to cause the same type of effects as a result of structural similarity.
In the case of BuMP, the hypothesis to apply the read-across approach is based on the structural similarity of the target compound BuMP with respect to the source compound MMP. Supporting information to further justify the analogue approach is provided by comparing the source and target compounds in terms of mechanistic similarity, physico-chemical properties, ADME profile and metabolism profiles.
Additional details can be found in the attached read-across study report.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to section 1.2 (general information/composition) of both target and source's IUCLID dossiers, and to the attached read-across study report.

3. ANALOGUE APPROACH JUSTIFICATION
Structural similartiy: he main structural difference between the target BuMP and the source MMP consists in the length of the alkyl chain esterifying the sulfanyl propanoate group, since in the source MMP the sulfanyl propanoate is linked to a methyl group, while in the target BuMP to a butyl group.
This difference is reflected in differences in molecular structure data (e.g., a greater no. of atoms and bonds in target with respect to the source). No structural differences in terms of functional groups, structural fragments and chemical class were identified, since the two compounds possess the same sulfanyl propanoate fragment. In particular, two functional groups were identified in the target BuMP and source MMP , i.e. Carboxylic acid ester and Thiol, and two ECOSAR chemical classes, i.e. Esters and Thiols.
Concluding, target and source compounds exhibited moderate structural similarity. Uncertainty associated with structural similarity was assessed to be low.

Mechanistic similarity: The target and source compounds exhibit moderate mechanistic similarity. In particular, the two compounds show a similar mechanistic profile with respect to protein binding potential, where the same alert was identified by the OASIS profiler ("Thiols and disulfide compounds") and the OECD profiler (“Thiols”) in both target and source (as illustrated in Figure 5.1). For this structural alert, it has been suggested an SN2 type mechanism with thiol groups in biological macromolecules resulting in the formation of disulfide bridges. Finally, the ACD/Acute Toxicity Hazards profiler did not identify any hazardous fragments that might be responsible for the acute toxicity of the compounds in rodents.
Concluding, target and source compounds exhibited high mechanistic similarity. However, the uncertainty associated with mechanistic similarity was assessed as medium, due to limitations associated with the endpoint type.

Physico-chemical similarity: From the analysis and comparison of experimental and in silico predicted physico-chemical data, it was noted that the target BuMP and source MMP have a similar profile; they are both determined by moderate to high water solubility (based on both experimental and in silico data), low volatile (VP <0.5 kPa and BP > 150 °C) and have similar lipophilicity (LogKow in the range 1-3), suggesting a similar dermal uptake. However, it is also noted that the water solubility of the source MMP is above 10.000 mg/l, suggesting that the chemical is more hydrophilic then the source. By considering also the LogKow for the source MMP being in the range 1 – 4, which is suggested to favour dermal absorption, it is considered that the source and the target will have similar dermal uptake.
Concerning dissociation, the target and source compounds show similar pKa values of 9.6, which refer to thiol groups that are very weak acids. It is expected that both compounds will exist mostly in the non-dissociated form at physiologically body-relevant pHs, i.e. pH 1.7 (stomach), 5 (skin), 7.4 (blood), with a positive impact on dermal absorption as well.
The estimated surface tension values of the source MMP and the target BuMP were noted to be above 10 mN/m (32.62 mN/m and 32.96 mN/m, respectively), indicating an unlikely enhanced effect on dermal uptake.
The liquid physical state of both chemicals highlights a readily uptake from the skin.
Based on the above considerations, the target BuMP is expected to be similarly absorbed from the skin as the source MMP.
Both, experimental and predicted data used in the present assessment were characterized by good reliability. In addition, a good consistency between experimental and predicted data was observed.
Concluding, the target and source compounds express moderate similarity in terms of their physico-chemical profile. The uncertainty associated with PC similarity was assessed as medium.

ADME similarity: Similarity with respect to ADME properties was assessed considering both available experimental data and in silico predicted data by ACD/Percepta. In this specific case, the assessment of the ADME similarity was based only on predicted data since experimental data were not available for target and source compounds. It was noted that the target BuMP is rather similar to the source MMP also in terms of their predicted ADME profile. In particular, the target and the source compounds were both expected to be well absorbed in the organism, with a predicted passive absorption across intestinal epithelium equal to 100%. This prediction is further supported by the physico-chemical properties of the two substances which are favorable for absorption by passive diffusion, i.e.: molecular weights below 500, moderate logKow values (between -1 and 4), and high solubility .
Both compounds were found to be characterized by high oral bioavailability (F greater than 90%, based on a standard administration dose equal to 50 mg), resulting from a good estimated solubility in the gastro-intestinal tract, good passive absorption across intestinal barrier, and a low predicted susceptibility to acid hydrolysis in stomach. However, it should be acknowledged that a significant first-pass metabolism was predicted for both compounds (55% and 49% of the absorbed fraction for target and source, respectively), meaning that there is a high probability that both substances will be metabolically transformed by enzymes in liver and intestine. In this way, the actual oral bioavailability declines to 44.9% and 50.9% for target and source, respectively.
Similar plasma protein binding potential (57.45% and 46.76%, respectively) and rather similar apparent volumes of distribution (4.3 and 2.2 L/Kg, respectively) are predicted for the target and source compounds. The volume of distribution of both compounds is above the volume of total body water (0.7 L/kg), and this indicates that both compounds have affinity to extravascular tissues.
Prediction of metabolic stability, i.e. t1/2 in Human Liver Microsomes, resulted to be undefined for both the target and source compounds, thus preventing the assessment of metabolism rate.
From the physico-chemical data analysis a similar dermal uptake is expected for the target BuMP, compared to the dermal uptake expected for the source MMP.
Concluding, the target and source compounds exhibit high similarity in terms of the predicted ADME profile. However, the uncertainty associated with ADME similarity was assessed to be medium, due to limitations associated to the following issues: i) assessment based only on predicted properties; ii) in silico data do not cover the whole ADME profile, e.g. rate and extent of metabolism and elimination.

Potential metabolic products: The major metabolites and biotransformation pathways of the target BuMP and source MMP were generated with the ChemTunes Liver BioPath tool, which predicts (and prioritize) metabolites of a compound deriving from human phase I and phase II reactions. Predicted metabolites generated by ChemTunes were integrated with the outcome of the OECD QSAR Toolbox skin metabolism simulator.
The major metabolites and biotransformation pathways of target and source compounds were generated with the ChemTunes Liver BioPath tool and the OECD QSAR Toolbox Skin metabolism simulator. From each parent compound, one metabolite is derived from the hydrolysis of the carboxylic acid esters (primary phase I reaction):
a) 3-sulfanylpropanoic acid (common phase I metabolite for the target BuMP and source MMP)
Conjugation via methylation of the thiol group is expected to occur as phase II metabolism for each of the two compounds.
The predicted metabolites from the OECD QSAR Toolbox skin metabolism analysis were the same as the phase I metabolites as provided by ChemTunes liver BioPath. A further metabolite (i.e., methanol and butanol) were predicted for BuMP and MMP by the OECD QSAR Toolbox.
Finally, the predicted metabolites of target and source compounds were profiled with the OECD QSAR toolbox (structural- and mechanistic-based profilers). The assessment of their structural and mechanistic similarity was performed in order to possibly understand whether some metabolites of the target might have an influence on the prediction of repeated dose toxicity. The results of this profiling are reported in Appendix A of the report, and are following summarised:
-The metabolites of the target and the source are structurally very similar. All identified structural features are the same for the target BuMP and the source MMP metabolites.
- There were also no major mechanistic differences identified among the target and the source metabolites concerning protein binding:
--The “Thiols” structural alert remains relevant for the common metabolite of the target and of the source, i.e. 3-sulfanylpropanoic acid (BuMP-M1 and MMP-M1). For this structural alert, it has been suggested a SN2 (nucleophilic substitution bimolecular reaction) type mechanism with thiol groups in biological macromolecules resulting in the formation of disulfide bridges (please refer to Figure 5.1 of section 5.4.2.1). No structural alerts for protein binding were identified in the remaining target and source metabolites.
--No hazardous fragments for acute oral toxicity were identified in any of the metabolites.

Supporting toxicological data: In the read-across study for acute dermal toxicity, it is considered important to integrate the information gathered also from other toxicological studies, i.e. skin irritation, skin sensitisation and acute oral toxicity. Toxicological data available for both sources (EHTG and MMP) were collected from the ECHA website. Skin irritation, skin sensitisation and acute oral toxicity experimental data were available for the two sources EHTG and MMP, and were predicted for the target compound EHMP by applying the QSAR models (QSAR predictions are reported in the attached report).
According to the available experimental data for the source (MMP), the compound is not a skin irritant neither skin sensitiser and is classified for acute oral toxicity category 3, based on the study in rat (LD50: 193.6 mg/kg bw). For the target BuMP, the predicted acute oral LD50 in rat was 330 mg/kg (predicted rat oral LD50 for MMP: 440 mg/kg). It was further predicted that BuMP is a skin sensitiser and a skin irritant, with moderate reliability. Skin irritation and skin sensitization predictions were generated also for the source MMP, which resulted as skin irritant and skin sensitizer as well. Thus, it is expected that the QSAR predictions provided for the target BuMP represent an overestimation of irritating and sensitising potential of BuMP.
Based on the evaluation of these toxicological endpoints, it is considered that the source MMP is more acutely toxic than BuMP after oral exposure, while it is expected that MMP and BuMP have similarirritating and sensitising properties.
Based on the assessment of the supporting toxicological data, it was concluded that MMP and BuMP have moderately similar toxicological profiles. Following, it is considered that for the target BuMP, MMP could be used as a source, thus supporting the rationale for the present read-across justification.
Source experimental data: for the assessment of acute dermal toxicity, one acute experimental study for MMP was available. The study for MMP was reported by the registrant to be reliable with restrictions (Klimisch 2). An experimental LD50 value of 1903.7 mg/kg bw was derived for the source MMP. Both studies were assessed as adequate for the read-across prediction of the target BuMP.

4. DATA MATRIX
The read-across analysis performed highlighted a moderate similarity in terms of structural similarity, physico-chemical data, mechanistic reasoning, ADME and toxicological profile between the target BuMP and the source MMP. The data matrix is included in the attached report.

Reason / purpose for cross-reference:

read-across source

Remarks:

Source MMP (CAS No. 2935-90-2)

Qualifier:

according to guideline

Guideline:

other: ECHA, 2015: Read-Across Assessment Framework (RAAF).

Specific details on test material used for the study:

SMILES: CCCCOC(=O)CCS
InChI: InChI=1S/C7H14O2S/c1-2-3-5-9-7(8)4-6-10/h10H,2-6H2,1H3

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 903.7 mg/kg bw

Based on:

other: Source MMP

95% CL:

>= 1 462 - <= 2 479

Remarks on result:

other: Read-across

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Based on read-across

Conclusions:

Acute dermal toxicity studies in rat and rabbit was available for the source MMP (rabbit - LD50 value 1903.7 mg/kg bw). Based on the read-across study presented, it is concluded that the acute dermal toxicity data available for the source could be used to support the same classification of the target BuMP. An overall moderat similarity was noted between the target BuMP and the source MMP which was used as the source.

Executive summary:

This study was designed to generate read-across predictions of acute dermal toxicity for BuMP to be used for its safety assessment in the regulatory framework of REACH.

In the read-across analysis, MMP was selected as source chemical for the target BuMP. The similarity assessment, which consisted of a comparison of structural, mechanistic, physicochemical, ADME and metabolism profiles, showed that the source MMP and the target BuMP are sufficiently similar to justify the read-across approach.

An acute dermal toxicity study in rabbit was available for the source MMP (LD50 value of 1903.7 mg/kg bw) and was assessed as adequate for the read-across prediction for the target BuMP.

In the present read-across study, an overall medium uncertainty was associated with similarity justification. However, the following issues were highlighted: i) mechanistic bases of the endpoint to be read-across are not yet well defined; ii) ADME assessment was based on simulated data only, which do not cover rate and extent of dermal and systemic metabolism and elimination; iii) identification of potential metabolites and related structural and mechanistic profiles was based on in silico predictions only. The main uncertainties associated with the read-across argument were related to the following issues: i) endpoint-type, ii) analogue set limited to one source compound.

Concluding, the read-across from the existing acute dermal toxicity study available for the source substance MMP could be used to predict the acute dermal toxicity of the target substance BuMP in order to fulfil the information requirement of Annex VIII 8.5 of the REACH Regulation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 905 mg/kg bw

Quality of whole database:

read across from valid study with MMP

Justification for classification or non-classification

Based on read across from MMP, BuMP is considered toxic if swallowed (LD50 = 194 mg/kg bw, Acute Tox 3 - H301) , toxic by inhalation (4-h LC50, vapour = 2.11 mg/L, Acute Tox 3 - H331), and harmful in contact with skin (LD50 = 1905 mg/kg bw, Acute Tox 4 - H312).

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