Methyl ester of fatty acids, Cx-Cy, Hydroxymethylated

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

In a local lymph node assay, the sensitization potential of the natural oil monomer (i.e., methyl polyhydroxymethyl stearate or MPS) was evaluated in female CBA/J mice. Mice treated with 5%, 20%, or 80% NOM displayed stimulation indices of 2.0, 3.2, and 7.4 in comparison to vehicle-treated mice. The concentration that would cause a 3-fold increase in proliferation (EC3) was calculated to be 17.5%, which is consistent with weak dermal sensitization potential as described by an expert ECETOC panel (Technical Report No. 87, 2003).

The LLNA results for NOM were unexpected. NOM is derived from a fatty acid methyl ester (FAME) product prepared from natural seed oils. Review of the FAME products safety information with the manufacturer (MSDS and personal communication) indicates a lack of sensitization potential. Not only are fatty acids endogenous molecules, but fatty acids and FAME are commonly used to enhance dermal penetration for drug delivery (Chukwumerije, et al., 1989; Kogan and Garti, 2006), without outbreaks of sensitization in the population. With that said, there are spurious reports of sensitization for some fatty acid-like molecules [isopropyl myristate (Uter, et al., 2004; Bharati and King, 2004), glyceryl stearate (de Groot, et al., 1988), isopropyl palmitate (Lazzarini, 1982), retinyl/retinol palmitate (Clemmensen, et al., 2007; Manzano, et al., 1994)], but these appear to be disproportional in number compared to the degree of use.

Evaluation of NOM using TOPKAT, DEREK and OASIS programs did not demonstrate an alert for sensitization potential (unreported data - The Dow Chemical Company).

The natural oil monomer was incubated with liver S9 to represent a worst-case scenario in the skin. The resulting samples were analyzed for the formation of an aldehyde metabolite, methyl polyformyl stearate, the mostly likely reactive species to be derived from NOM. No aldehyde-containing metabolites were found to arise from in vitro metabolism of NOM.

A guinea pig M&K test was conducted and the first induction phase involved six intradermal injections into the suprascapular area of each of 20 guinea pigs using paired injections of the test substance in mineral oil (5% w/w), the test substance (5% w/w) combined with Complete Freund's Adjuvant as well as Complete Freund's Adjuvant alone. Approximately one week later, the second phase of induction applied undiluted MPS topically for a period of 48 hours to the area encompassing the intradermal injection sites. Subsequent topical challenge using 6% NOM did not elicit evidence for sensitization potential.

The expression of relevant lymphocyte surface markers (B220+) and mouse ear swelling responses following previous dermal induction was evaluated. The results of the B220+ assay suggest that the proliferative response tomethyl polyhydroxymethyl stearate in the draining lymph node is consistent with that of a chemical having skin sensitizing potential. Similarly, the MEST demonstrated ear swelling upon specific challenge with MPS that was indicative of a sensitization response. The B220+ and MEST responses following topical treatments with MPS are generally consistent with the mouse LLNA. These studies in mice, collectively, suggest that methyl polyhydroxymethyl stearate may possess weak dermal sensitization potential.

Migrated from Short description of key information:
The concentration that would cause a 3-fold increase in proliferation (EC3) was calculated to be 17.5%, which is consistent with weak dermal sensitization potential as described by an expert ECETOC panel (Technical Report No. 87, 2003).

Justification for classification or non-classification

NOM demonstrates a somewhat inconsistent profile, but may possess weak for dermal sensitisation potential (R43). The substances has no evidence to suggest that it should be classified for respiratory sensitisation.