2,2-bis[[(mercaptoacetyl)oxy]methyl]-1,3-propanediyl bis(mercaptoacetate)

Endpoint summary

Description of key information

There is sufficient information from experience in humans that PETMP is a skin sensitizer. Based on read-across approach, PETMA can also be considered as skin sensitizer.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

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

Adequacy of study:

supporting study

Study period:

1977

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: non guideline, non-GLP, but with sufficient reporting detail to accept the positive result

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 PETMA, the hypothesis to apply the read-across approach is based on the similarity of the target compound PETMA with respect to the source compound PETMP. Similarity analysis is performed in terms of structural and mechanistic similarity. Supporting information to further justify the analogue approach is provided by comparing the source and target compounds in terms of physico-chemical properties and ADME profile (including metabolism).

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 read-across study report attached.

3. ANALOGUE APPROACH JUSTIFICATION
Structural similarity: Minimal structural differences were identified between the target and the source compounds. In particular, the source possesses a tetrahydroxy neopentyl esterified with four sulfanyl propanoate groups, while target is a tetrahydroxy neopentyl esterified with four sulfanyl acetate groups. These differences are reflected in minimal differences in molecular structure data, e.g. no. of atoms and bonds. No differences were identified in terms of functional groups and structural fragments by the structure-based profilers. Finally, the same chemical classes have been identified by the ECOSAR classification system, i.e. Esters and Thiols. Concluding, the target and the source compounds exhibited high structural similarity. Uncertainty associated with structural similarity was assessed as low.

Mechanistic similarity: Both the OECD QSAR Toolbox and ACD/Percepta were employed to profile the source chemical, i.e. PETMP, as well as target substance PETMA, in order to describe their foreseen mechanism of action relevant for skin sensitization. A high mechanistic similarity was noticed for the target and source compounds. In particular, the two compounds showed a similar mechanistic profile with respect to the protein binding potential. In fact, the same “Thiols” structural alert, corresponding to R-SH (where R = any carbon), was identified by the OASIS and OECD profilers, in both the target and source compounds. 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. The Toxic Hazards Classification by Cramer (extension) of the OECD QSAR Toolbox assigned a High (Class III) classification to both the target and source compounds. The High (Class III) category refers to substances with chemical structures that permit no strong initial presumption of safety, or may suggest significant toxicity, and/or substances with reactive functional groups. In this case, both target and source compounds were found to fail the Cramer Question No. 33 of the decision tree implemented in this profiler, where a lack of sufficient number of sulphonate or sulphamate groups was recognised. In general, Na, K, Ca sulphonate and sulphamate salts are known to have a strong tendency to decrease toxicity by promoting solubility and rapid excretion, and therefore sulphonated compounds are deemed to be less toxic than unsulphonated compounds, as PETMA and PETMP. However, no additional rules leading to a High (Class III) assignment were found to have been satisfied. Finally, the ACD/Acute Toxicity Hazards profiler did not identify any hazardous fragment that might be responsible for the acute toxicity of the compounds in rodents.
Concluding, the target and source compounds were characterised by high mechanistic similarity. However, the uncertainty associated with this mechanistic similarity was assessed as moderate, 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 PETMA and the source PETMP exhibited a similar profile. Both compounds have a vapour pressure of <0.5 kPa and a boiling point above 150°C, indicating the low volatility of both substances. Both target and source compounds are moderately lipophilic with moderate LogP values (LogKow in the range 2 - 3). An experimental moderate solubility for the target PETMA was noted (in agreement with the QSAR prediction), whereas a slight solubility was experimentally recorded for the source PETMP (predicted as moderately soluble). Concerning dissociation, both source and target compounds showed a pKa value close to 9, because of the thiol groups which are very weak acids. In fact, it is expected that both compounds will exist in the non-dissociated form at physiologically body-relevant pHs, i.e. pH from 1.7 (stomach) to 7.4 (blood) and 8.0 (colon).
Both experimental and predicted data, used in the present assessment, were characterized by good reliability, with the only exception of the water solubility (ACD/LogS0 GALAS) prediction for the target, which was assessed to be borderline reliable. Generally, a good consistency between experimental and predicted data was observed, with the exception of the water solubility results for the source.
Concluding, the target and the source compounds exhibited high similarity in terms of their physico-chemical profile. The uncertainty associated with PC similarity was assessed as low.

ADME similarity: the ADME property similarity was assessed based on predicted data by ACD/Percepta for absorption, bioavailability, distribution, and metabolism. It was noted that the target PETMA was rather similar to the source PETMP in terms of their predicted ADME profile. In particular, as also anticipated by their moderate LogP values, target and source compounds were both predicted to be well absorbed in the organism, with an estimated passive absorption across intestinal epithelium via transcellular route equal to 100%. For both compounds ACD/Percepta predicted a high oral bioavailability, i.e. F greater than 99% (based on a standard administration dose equal to 50 mg), resulting from a good estimated solubility in the gastro-intestinal tract, good passive absorption of the human intestinal membrane, 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 (94% and 98% of the absorbed fraction for target and source, respectively), meaning that there is a high probability that both substances will be metabolically transformed by hepatic and intestinal enzymes. In this way, the actual oral bioavailability declines to 6% and 2% for target and source, respectively. Similar and high plasma protein binding potential (78.83% and 85.93%, respectively) and similar apparent volumes of distribution (1.1 and 4.6 L/kg, respectively) were 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 could 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.
Concluding, the target and the source compounds exhibited high similarity in terms of the predicted ADME profile. However, a medium uncertainty was associated with the predicted ADME similarity, due to following limitations: 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/elimination.

Potential metabolic products: The major metabolites and biotransformation pathways of target PETMA and source PETMP were generated with the ChemTunes Liver BioPath tool. For both target and source compounds, the primary phase I reaction consists in the hydrolysis of one of the carboxylic acid esters. The metabolites of the target and source were structurally similar, even though the chain structure of the source’s metabolites was characterised by an additional single carbon-carbon bond in respect of the chain structure of the target’s metabolites. Of course this difference was a reflection of the parent compounds’ structures (sulfanyl acetate groups in the target and sulfanyl propanoate groups in the source). Concerning phase II metabolism, conjugation was predicted for both target and source compounds via methylation of one of the thiol groups. 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 hazard). 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 oral toxicity. No structural and mechanistic differences were identified among the target and source metabolites in terms of their functional groups and chemical classes. Further information on metabolites identification and profiling are included in the attached report. Concluding, target and source compounds exhibited high similarity in terms of their potential metabolites. In turn, the identified potential metabolites showed high structural and mechanistic similarity. The uncertainty associated with the identification of potential metabolic products was assessed as low. However, it is worth noting that the identification of potential metabolites and related structural and mechanistic profiles was solely based on in silico predictions.

Source experimental data: for the assessment of skin sensitization, experimental data in guinea pigs performed with the source substance PETMP was available. The study has been reported by the registrant to be reliable with restrictions (Klimisch score 2), non-guideline, non-GLP, but with sufficient reporting detail to accept the positive result. Based on the study results, PETMP is a strong skin sensitizer in GPMT and needs to be classified as Skin sens. 1A. This study was assessed as adequate for the read-across prediction of the target PETMA.

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

yes

Remarks:

A reliability check was not included; this is not necessary in light of the positive result. The test material was not characterised.

GLP compliance:

no

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

An guinea pig maximisatoin test is used. Due to animal welfare no LLNA test system was conducted.

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

female

Route:

intradermal and epicutaneous

Vehicle:

petrolatum

Concentration / amount:

Induction: 1% (intradermal), 20% (topical)
Challenge: 0.5, 1, 5, 10%

Route:

epicutaneous, occlusive

Vehicle:

petrolatum

Concentration / amount:

Induction: 1% (intradermal), 20% (topical)
Challenge: 0.5, 1, 5, 10%

No. of animals per dose:

20

Group:

positive control

Remarks on result:

not measured/tested

Group:

negative control

Remarks on result:

other: not reported

Reading:

other: two readings combined

Hours after challenge:

48

Group:

test chemical

Dose level:

0.5%

No. with + reactions:

19

Total no. in group:

20

Reading:

other: two readings combined

Hours after challenge:

48

Group:

test chemical

Dose level:

1%

No. with + reactions:

20

Total no. in group:

20

Reading:

other: two readings combined

Hours after challenge:

48

Group:

test chemical

Dose level:

5%

No. with + reactions:

20

Total no. in group:

20

Reading:

other: two readings combined

Hours after challenge:

48

Group:

test chemical

Dose level:

10%

No. with + reactions:

20

Total no. in group:

20

Interpretation of results:

Category 1A (indication of significant skin sensitising potential) based on GHS criteria

Conclusions:

Based on a read-across to PETMP, PETMA is a strong sensitizer in the GPMT

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

 

 

 

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

Regarding respiratory sensitisation, no evaluated testing procedures are available. Testing of the endpoint is not required according to REACh.

Justification for classification or non-classification

Based on read-across to PETMP, PETMA is considered as strong skin sensitizer. Therefore, PETMA will be classified as Skin Sens. 1A. H317. May cause an allergic skin reaction.