Reaction mass of didodecyl 3,3'-thiodipropionate and dioctadecyl 3,3'-thiodipropionate and octadecyl 3-[[3-(dodecyloxy)-3-oxopropyl]thio]propionate

Endpoint summary

Description of key information

Based on read across from E12 and E18, E1218 is non-toxic via the oral and dermal route. Inhalation exposure is unlikely considering the very low vapour pressure of E1218.

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 read-across justification attached as "full study report"

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Principles of method if other than guideline:

read across from E12 and E18 using the OECD QSAR Toolbox 4.2

Species:

rat

Route of administration:

other: Oral: Gavage Oral: Unspecified

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

5 500 mg/kg bw

Based on:

other: read across from E12 and E18

Interpretation of results:

GHS criteria not met

Conclusions:

Based on read across from E12 and E18, E1218 is non-toxic via the oral route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Read across from valid studies with E12 and E18

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

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:

Many-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. many-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 current study, dilauryl thiodipropionate (E12) and distearyl thiodipropionate (E18) were selected as source chemicals for the read-across prediction of acute dermal toxicity for the target E1218. The three substances are members of the same intramolecular-S family (derived from Thiodiglycolic acid, Thiodipropionic acid, Dithiodiglycolic acid or Dithiodipropionic acid). In particular, the sources E12 and E18 are a mono-constituent substances, while the target E1218 is a multi-constituent substance, being a mixture of three esters E12, E18 and E1218 (dilauryl stearyl thiodiproprionate). It is highlighted that two target constituents (i.e., E12 and E18) are identical to the mono-constituent source substances E12 and E18, while the remaining target constituent E1218 belongs to the same “pool” of structurally related constituents. Thus, according to the RAAF guidance for UVCB and MCSs , structural similarity as a basis for the read-across may be assumed. As explicated in the RAAF guideline for multi-constituent substances and UVCBs, the impact of the combined exposure of different constituents on the type and strengths of effects (due to possible interaction among the constituents), along with a comprehension of their individual potency, will be considered to assess the prediction for the target substance.
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 and ADME profile.
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 similarity: No significant structural differences in terms of functional groups and chemical class were identified, since all compounds share the 3,3'-sulfanediyldipropanoate fragment, which is esterified with aliphatic alkyl chain of different length (C12 and/or C18). For all the analysed structures, two functional groups, i.e. Carboxylic acid ester and Sulfide, and the ECOSAR chemical class of Esters was identified. The main structural difference among the sources and target is represented by the carbon chain length of the two lateral chains (C12 for the source and target constituent E12, C18 for the source and target constituent E18, and C12/C18 for the target constituent E1218). This difference is reflected in minimal differences in molecular structure data (i.e., different no. of atoms and bonds).
Concluding, the target and source substances exhibit high structural similarity. Uncertainty associated with structural similarity was assessed to be low.

Mechanistic similarity: The target and source compounds exhibited high mechanistic similarity. As it can be noted from the table above, no structural alerts for protein binding potential nor hazardous fragments for acute systemic toxicity were identified in the three analysed structures.
Concluding, the target and source substances 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, no major differences are noted between target and source substances. As expected from their chemical structure characterised by rather long chains of carbon atoms, both substances were predicted to be highly hydrophobic and insoluble, with LogKow values greater than 10 and water solubility (experimental and predicted) below 1 mg/L. Since no dissociating groups are found in both structures, pH has no influence on LogKow, water solubility, and ADME properties. Lastly, volatilisation is not expected to occur for both substances.
It is highlighted that several properties of E12, E18 and E1218 are not favourable for dermal uptake, including the solid physical state, molecular weights above 500 g/mol, low water solubility (<1 mg/L), high lipophilicity (LogKow > 6), no surfactant properties. The low volatility (VP <0.5 kPa) is not expected to affect dermal uptake.
The majority of physico-chemical data used in the present assessment are characterised by good reliability (Klimish 2 experimental studies as well as moderately reliable QSPR predictions), with the exception of few predicted data (i.e., LogKow predictions for E1218 and E18 and water solubility predictions for both target and source) characterised by borderline reliability. In addition, a good consistency between experimental and predicted data was observed for the target and source substances.
Concluding, the target and source compounds exhibited high similarity in terms of their physico-chemical profile. Specifically, very high hydrophobicity, low water solubility, no volatilisation potential were observed in all substances. The uncertainty associated with PC similarity was assessed to be low.

ADME similarity: Permeability depends on lipophilicity, degree of ionization and molecular size. Moreover, passive transport generally increases with increasing LogKow values up to 3.5, but declines thereafter (Liu and Hunt 2005). As discussed above, target and source substances are highly lipophilic and insoluble molecules with a molecular weight greater than 500 Da, and with no dissociating properties.
Experimental toxicokinetic studies were available for E12 and E18 (source substances and target main constituents). Both studies were assessed to be reliable with restrictions (Klimisch 2) by the data owner, and were based on three publications (Reynolds et al. 1974 , Liebert 1992 , and Diamante et al. 2011 ). The studies were conducted according to guideline equivalent or similar to the OECD TG 417 (Toxicokinetics), where the fate of the two substances after oral application to rats was investigated. The main results are reported in the table above and following summarized:
- both E12 and E18 were found to be almost entirely absorbed from the gastrointestinal tract.
- distribution in tissues was reported to be close to normal values except the value of radioactivity in the fat, which was found to be elevated at 4 days after dosing and remained so at 8 and 34 days.
- the metabolite dithiopropionic acid was recovered in urine free or as an acid-labile conjugate.
- elimination occurred mostly via urine (up to 88 and 90%, for E12 and E18, respectively); more than 90% of the dose was eliminated within 24 h.
As far as concern the similarity analysis based on in-silico ADME properties, a similar ADME profile was noted for the target E1218 and the sources E12 and E18. In particular, the three compounds were predicted to cross a biological membrane by transcellular mechanisms, resulting in an optimal passive absorption across intestinal epithelium (i.e., HIA 100%). The good absorption from the gastrointestinal tract predicted for E12 and E18 find confirmation in the experimental studies mentioned above.
A very poor oral bioavailability, and thus a very low amount of substance that reaches systemic circulation after oral administration (%F), was predicted for all compounds. This was due to the estimated chemicals’ low solubility in the gastro-intestinal tract, low susceptibility to the stomach decomposition, and significant first-pass metabolism, which represents the probability that substances will be metabolically transformed by enzymes in liver and intestine. In general, passive absorption does not affect the %F.
Target and source chemicals were also characterized by volumes of distribution above the volume of total body water of 0.7 L/kg (Vd increasing with the increase of carbon chain length). This suggests that the three compounds have affinity to extravascular tissues. Affinity for fat tissue was found experimentally for both E12 and E18. Predictions of plasma protein binding resulted not reliable for all the structures.
Prediction of metabolic stability, i.e. t1/2 in Human Liver Microsomes, resulted to be undefined for target and source compounds, thus preventing assessment of metabolism rate. Prediction of potential metabolites is discussed in the following paragraph.
Finally, no in silico data are available for estimating the elimination rate. However, experimental data available for E12 and E18 indicate that more than 90% of the dose is eliminated within 24h.
Concluding, target and source compounds exhibited high similarity in terms of their predicted ADME profile. In addition, the predicted ADME profile for the target and source compounds is in agreement with available toxicokinetic data for the two sources E12 and E18. Overall, the uncertainty associated with ADME similarity was assessed to be low.
Additional considerations for multi-constituents and UVCB: As commented in the mechanistic reasoning paragraph, no interactions are expected among the target constituents (no reactive groups/alerts were identified in the target and source structures). Thus, no variations in physico-chemical properties and toxicokinetics are expected due to interactions among target’s constituents.

Potential metabolic products: Two phase I reactions are predicted for the structures E1218, E12 and E18:
- hydrolysis of the carboxylic acid ester, leading to the formation of the acids 3-{[3-(dodecyloxy)-3-oxopropyl]sulfanyl}propanoic acid (for E1218 and E12) and 3-{[3-(octadecyloxy)-3-oxopropyl]sulfanyl}propanoic acid (for E1218 and E18), and the related alcohols dodecan-1-ol (for E1218 and E12) and octadecan-1-ol (for E1218 and E18);
- sulphide oxidation, leading to the formation of dodecyl octadecyl 3,3'-sulfinyldipropanoate and dodecyl octadecyl 3,3'-sulfonyldipropanoate (for E1218), didodecyl 3,3'-sulfinyldipropanoate and didodecyl 3,3'-sulfonyldipropanoate (for E12), dioctadecyl 3,3'-sulfinyldipropanoate and dioctadecyl 3,3'-sulfonyldipropanoate (for E18). The products of sulphide oxidation are then predicted to undergo to hydrolysis of the carboxylic acid ester
If a 2nd level of metabolism was included in the Liver BioPath simulation, the same metabolites predicted by the OECD QSAR Toolbox/Skin metabolite simulator were identified, as well as Phase II metabolites (via glucuronidation) were predicted. In addition, it is highlighted that the metabolite thiodipropionic acid was among the 2nd level predicted metabolites with higher odds ratio via hydrolysis of the carboxylic acid ester. The presence of this metabolite is confirmed by the toxicokinetics studies performed with E12 and E18.
Finally, the predicted metabolites of target and source compounds were profiled within the OECD QSAR toolbox (structural- and mechanistic-based profilers) and ACD/Percepta (ACD/Acute Toxicity Hazards). 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 acute dermal toxicity. The results of this profiling are reported in Appendix A of the attached report, and are following summarised:
- No relevant structural differences were identified among the target and source metabolites in terms of functional groups and chemical classes.
- No mechanistic differences were identified among the target and source metabolites concerning protein binding and ACD/Percepta Acute Toxicity Hazards. In fact, no structural alerts for protein binding nor for systemic acute oral toxicity were identified in all target and source metabolites.
Concluding, the target and source substances exhibited high similarity in terms of their potential metabolites. In particular, the fact that both substances are likely to undergo to ester hydrolysis find confirmation in experimental toxicokinetic studies. The predicted metabolites showed high structural and mechanistic similarity. Thus, the uncertainty associated with the identification of potential metabolic products was assessed to be low.

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 the sources E12 and E18 were collected from the ECHA website. Skin irritation, skin sensitisation and acute oral toxicity were predicted for the target’s constituents by applying the QSAR models (QSAR predictions are detailed in the attached report). Both source substances E12 and E18 exhibit a low toxicity profile, being not skin irritant, not skin sensitizing and with oral acute LD50 greater than 2000 mg/kg. Skin irritation and acute oral toxicity experimental data available for E12 and E18 are consistent with QSAR predictions generated for the two compounds. In fact, both E12 and E18 are predicted as not skin irritant, with moderate to high level of confidence, and their predicted LD50 values are largely above 5000 mg/kg. Differently, QSAR predictions for skin sensitization are not consistent with the experimental data, since both E12 and E18 are predicted to be skin sensitizers with a moderate level of confidence.
As expected, the QSAR predictions generated for E12 and E18 are similar to E1218 predictions.
Based on the evaluation of the supporting experimental toxicological data available for the source substances E12 and E18, which are also two target’s constituents, it is expected that the toxicological profile of the target E1218 is similar to the toxicological profile of the two sources E12 and E18.

Source experimental data: for the assessment of acute dermal toxicity, one acute experimental study for each of the two source substances E12 and E18 was available. Both studies were reported by the registrant to be reliable without restrictions (Klimisch score 1), and they both resulted in experimental LD50 values greater than 2000 mg/kg bw. Both studies were assessed as adequate for the read-across prediction of the target E1218.

4. DATA MATRIX
Data matrix is included in the attached report.

Reason / purpose for cross-reference:

read-across source

Remarks:

Source 1 E12 (CAS No. 123-28-4)

Reason / purpose for cross-reference:

read-across source

Remarks:

Source 2 E18 (CAS No. 693-96-7)

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

other: ECHA, 2017: Read-Across Assessment Framework (RAAF). Considerations on multi-constituent substances and UVCBs.

Specific details on test material used for the study:

SMILES: O=C(OCCCCCCCCCCCC)CCSCCC(=O)OCCCCCCCCCCCCCCCCCC
InChI=1S/C36H70O4S/c1-3-5-7-9-11-13-15-16-17-18-19-20-22-24-26-28-32-40-36(38)30-34-41-33-29-35(37)39-31-27-25-23-21-14-12-10-8-6-4-2/h3-34H2,1-2H3

Key result

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

other: Source 1

Remarks on result:

other: Read-across

Key result

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

other: Source 2

Remarks on result:

other: Read-across

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

Based on read-across

Conclusions:

Based on the read-across study presented, it is concluded that the acute dermal toxicity data available for E12 and E18 (source 1 and source 2, respectively) could be used to support the same conclusion of no classification for the target E1218.

Executive summary:

This study was designed to generate read-across predictions of acute dermal toxicity for the multi-constituent substance Lauryl stearyl thiodiproprionate (E1218) to be used for its safety assessment in the regulatory framework of REACH. The target E1218 (trade name Evanstab™ 1218) is a mixture of 3 esters: dilauryl thiodipropionate (E12, or DLTDP), distearyl thiodipropionate (E18, or DSTDP), and the mixed ester dilauryl/stearyl thiodipropionate.

In the read-across analysis, E12 and E18 (mono-constituent substances) were selected as source chemicals for the target E1218. Two target constituents (i.e., E12 and E18) are identical to the source substances E12 and E18; one target constituent (i.e., E1218) belongs to the same “pool” of structurally related constituents. Thus, according to the RAAF guidance for UVCB and MCSs, structural similarity as a basis for the read-across may be assumed.The similarity assessment, which consisted of a comparison of structural, mechanistic, physicochemical, ADME and metabolism profiles, showed that the sources E12 and E18 are sufficiently similar to the target E1218 to justify the read-across approach. In particular, a similar dermal absorption (low) and metabolism (hydrolysis of the ester and possible sulphide oxidation) are expected for the three substances, suggesting that the target bioavailability after dermal exposure is similar to bioavailability of the source compounds.

Key experimental acute dermal toxicity studies were available for the sources E12 and E18; the two studies were assessed as adequate for the read-across prediction for the target E1218.

Supporting toxicological data for endpoints relevant for acute dermal toxicity (i.e., skin irritation, skin sensitization and acute oral toxicity) were analysed in order to further support the read-across prediction and likely contribute to the reduction of its uncertainty. Both experimental data (available for the sources E12 and E18) and QSAR predictions (generated for E1218, E12 and E18) were considered. E12 and E18 exhibited a low toxicity profile, being not skin irritant, not skin sensitizing and with oral acute LD50 greater than 2000 mg/kg. Experimental data were consistent with QSAR predictions generated for E12, E18 and E1218, except for the endpoint skin sensitization, since the three compounds were predicted as skin sensitizers. However, it is expected that the skin sensitization predictions are over estimation of actual sensitization potential.

In the present read-across study, an overall low uncertainty was associated with similarity justification. However, the following issue was highlighted: the endpoint to read-across does not have yet well-defined mechanistic bases. The main uncertainties associated with the read-across argument were related to the following issues: i) endpoint-type, ii) no bridging studies among the source and the multi-constituent target. However, no interactions among target’s constituents are expected.

Concluding, the read-across from the acute dermal toxicityexperimental studies which are available forthe source substances E12 and E18, are likely to predict the acute dermal toxicity of the target substance E1218 and are considered as adequate to fulfil the information requirement of Annex VIII 8.5 of the REACH Regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Read across from valid studies with E12 and E18

Justification for classification or non-classification

The LD50 of E1218 via the dermal and oral route is assumed to be greater than 2000 mg/kg bw.