Octanoic acid, 1,1'-(1,3-propanediyl) ester

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

For a chemical to induce skin sensitization, it must not only cross the stratum corneum of the skin in sufficient quantities but also form a covalent bond with a skin protein (Barratt et al, 1997). The hypothesis for (Q)SAR models is that the skin protein behaves as a nucleophile and the chemical as an electrophile (Aptula et al, 2005). The electrophilicity may be an intrinsic property of the chemical, the result of auto-oxidation or the result of xenobiotic metabolism in the skin (Barratt et al, 1997; Smith et al, 2003; Enoch et al, 2008). Protein binding occurs via reaction pathways such as SN2, Michael addition, acylation or Schiff base formation.

The structure of 1,3-propanediol dicaprylate was compared to the structural alert rules published by Gerner et al (Gerner et al, 2004). It was also investigated for protein binding using the OECD toolbox (Version 1.1, 2008). Metabolism in skin was predicted based on the presence of enzymes described by Oesch et al (Oesch et al, 2007). Experimental data provided by the registrant were assessed for information regarding intrinsic reactivity and skin sensitization. Public databases such as TOXNET and the OECD toolbox were screened for information on structurally related chemicals.

 

Assessment:

1,3-Propanediol dicaprylate/dicaprate (CAS# 1072005-10-7 referred as source substance) is proposed as structural analogue for the target substance 1,3-propanediol dioctanoate (CAS# 56519-71-2). Both substances are diesters with 1,3-propanediol of similar molecular size, containing the same functional groups. Due to the lack of human health data on skin sensitisation by 1,3-propanediol dioctanoate, a skin sensitisation study with the source substance is suggested to be used for closing the respective data gap in the target substance dossier.

The structural analogue 1,3 propanediol dicaprylate/dicaprate was tested in a GLP study performed according to OECD guideline 429 (Huygevoort et al., 2009). Groups of five young adult CBA/J mice were treated epidermally with 25 µl/ear of doses of 25, 50 and 100% in acetone/olive oil (4:1 v/v) once daily for three consecutive days. Three days after the last induction, the mice were injected with 3H-methylthymidine and the lymphn nodes were prepared five hours later. As results, the mean DPM/animal values for the experimental groups treated with test substance concentrations 25, 50 and 100% were 980, 1152 and 1966 respectively. The mean DPM/animal value for the vehicle control group was 751. The SI values calculated for the substance concentrations 25, 50 and 100% were 1.3, 1.5 and 2.6 respectively. As all SI values were <3, 1,3 propanediol dicaprylate/dicaprate can be regarded as not sensitizing to skin.

Similarities in structure and physico-chemical properties of the source and target substance are supposed to form a basis for the analogue approach. In the case of this endpoint, chemical structures are investigated with respect to the presence or absence of structural alerts, indicating protein binding affinity. As the profiles of both substances are identical and indicate no sensitisation potency, the read-across for this endpoint is justified based on the structural similarity structural alert based profiles of both, target substance and source substance.

 

This is supported by the fact, that no structural alert for intrinsic protein binding properties was identified both by structural alert rules and the OECD tool box. Saturated aliphatic esters are not associated with sensitizing properties. Assessing skin metabolism, 1,3-propanediol dicaprylate is expect to undergo rapid enzymatic ester hydrolysis (Oesch et al, 2007). For the hydrolysis products 1,3-propanediol and octanoic acid experimental data is available: 1,3-Propanediol does not cause skin sensitization in guinea pigs (Til et al, 1979) and in humans (Eisenberg et al, 2007; Mark et al, 2006) and octanoic acid does not cause skin sensitization in the local lymph node assay in mice (Basketter et al, 1998). 1,3-propanediol dicaprylate does not contain double bonds that may lead to peroxides or epoxides upon oxidation. Therefore, no sensitizing auto-oxidation products are expected. The known by-products of 1,3-propanediol dicaprylate do not give rise of concern for sensitizing properties.

Migrated from Short description of key information:
1,3 propanediol dicaprylate is considered to be non-sensitizing. This assessment is based on experimental data on the structural analogue 1,3 propanediol dicaprylate/dicaprate and the metabolites propane-1,3-diol and octanoic acid as well as absence of structural alerts.

Justification for classification or non-classification

The results are conclusive but not sufficient for the classification of Propanediol Dicaprylate with regard to skin sensitization.