Hexanedioic acid, 1,6-bis(2-propylheptyl) ester

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Dipropylheptyladipat was assessed for its skin sensitising potential using the Local Lymph Node Assay (LLNA) in mice. Test item solutions at different concentrations (10, 25, and 50% (w/w)) were prepared in the vehicle acetone:olive oil (4+1, v/v). The highest concentration tested was the highest concentration that could be achieved whilst avoiding systemic toxicity and excessive local skin irritation (as determined by a pre-experiment). A statistically significant or biologically relevant increase in ear weights was not observed in any treated group in comparison to the vehicle control group. Furthermore, for BALB/c mice, a cutoff-value of 1.1 for the ear weight index was reported for a positive response regarding ear skin irritation. The index of 1.12 determined for the high dose group reached this threshold, indicating a marginal borderline positive response for ear skin irritation. But the index obtained did not exceed the threshold of 1.25 for excessive irritation stated in the OECD. A test item is regarded as a sensitiser in the LLNA if exposure to one or more test item concentration results in a 3-fold or greater increase in the Stimulation Index (S.I.). In this study an S.I. of 3.70 were determined with the test item at concentrations of 50%. Furthermore, the cutoff-value of 1.55 for a positive response regarding the lymph node cell count index reported for BALB/c mice was exceeded in the high dose group and the test itemwas found to be a weak skin sensitizerand anEC3 value of 39.2 %(w/w) was derived (Harlan 2013).

However, for the structural analogue of Dipropylheptyladipat, Diethylhexyladipat, there were no indications for a skin sensitizing potential in animal studies. Ten male guinea pigs were treated with intracutaneous injections into the dorsal skin. On the first day, 0.05 mL of a solution containing 0.1% test item in olive oil. For the next 3 weeks injections were performed 3 times a week with 0.1 mL of the same solution. After 14 days the intradermal challenge with 0.05 mL of the 0.1 % test item containing solution gave no indication for skin sensitizing properties. The area and height of the reaction was measured 24 hours after the challenge dose. The average area and height of the reaction at challenge were smaller than during induction and the test item was found not to be a skin sensitizer (CFTA 1967). Furthermore, undiluted Diethyhexyladipat did not show skin sensitizing effects in a patch test with rabbits (Mallette 1952). These results were confirmed by using the validated quantitative structure-activity relationship (QSAR) software, OASIS-LMC, that predicted both the parent compound and its metabolites as non-sensitiser (BASF 2008).

Additionally, the LLNA was shown to overestimate the skin sensitizing potential of some long-chain carbonic acids and their esters as well as fatty alcohols (Kreiling et al., Food and Chemical Toxicology 46 (2008) 1896 -1904; Anderson et al., J Allergy 2011, Article ID 424203; Basketter et al., Contact Dermatitis 60 (2009) 2:65 -69) possessing molecular structures similar to Dipropylheptyladipat.

Thus, the dermal sensitizing potential of Dipropylheptyladipat was investigated according to the methods of the OECD guideline 406 (1992) in a guinea pig maximization test (GPMT) by MAGNUSSON and KLIGMAN (1970). Two main studies were performed with 5 animals per control group and 10 animals per test group. The test concentrations for the first main study were selected on the basis of the results of the preliminary investigations regarding dermal exposure and intradermal injection. Two main studies were conducted with an intradermal induction with 5% of the test item in olive oil (day 0) followed by a dermal induction with the undiluted substance (day 7). In the first main study a dermal challenge (day 21) was performed with the undiluted substance and a rechallenge (day 28) with 75% of the test item in olive oil while for the second main study a challenge with 75% and rechallenge with 50% of the test item in olive oil were used. During the two main studies, animals of both the control groups and the test groups responded with slight skin reactions to the treatment with the 75% or 100 % test item. These findings were confirmed by the rechallenges. Since the incidence and severity of the skin reactions in the control and the test groups were comparable in the first main study while the incidence of skin reactions was even higher in the control than in the treated animals during the second main study, the Dipropylheptyladipat was sufficiently shown not to be a skin sensitizer (FREY-TOX 2014).

Migrated from Short description of key information:
Dipropylheptyladipat was weakly sensitizing in the mouse local lymph node assay but not sensitizing in the guinea pig maximization test verified by a second main study and a rechallenge. Considering supporting information from a structural analogue, the structure of Diethylhexyladipat did not give any indication forsensitizing properties (for both the parent and metabolites) in a quantitative structure-activity relationship (QSAR) analysed by means of the validated OASIS-LMC. Furthermore, the available information from animal studies, a patch test with rabbits and a Draize test with guinea pigs, did not indicate a skin sensitising effect of Diethylhexyladipat.

Justification for classification or non-classification

Based on the available data, Dipropylheptyladipat does not have to be classified for skin sensitisation according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP/GHS).