Risk assessment of oral exposure to cyclic siloxanes - octamethylcyclotetrasiloxane (D4) as an example.

Published data on in vivo toxicity of octamethylcyclotetrasiloxane (D4) on rat kidneys was re-evaluated. It turned out that a molecular and biochemical mode of action (MOA) of D4 induced effects on kidneys and its human relevance is missing, which remains a gap in current knowledge. Increased kidney weights (also in recovery groups) were considered as D4 specific adverse effects. In vitro, cytotoxicity was observed for D4 in human (HEK293, CaKi-1) and canine (MDCK) kidney cell lines, while no toxicity was observed in human hepatic cell line HepG2. Proteomic profiling at low toxic doses, using KEGG pathway analysis revealed that proteins in ribosomes, t-RNA biosynthesis and carbon metabolism were down-regulated in HEK293 cells. This indicates, that main cellular processes were disturbed. In HepG2 cells, DNA replication was affected, but no decrease in cell viability occurred. A BMDL5 value of 84 ppm for the kidney weight increases after chronic inhalation of D4 in rats was derived. The BMDL5 was converted to an oral TDI of 0.21 mg/kg bw per day, using standard factors. This corresponds to a specific migration reference value of 13 mg/kg food, which is applicable for food contact materials. Due to missing data on higher cyclic siloxane oligomers, but an expected similar toxicological profile, this reference value was applied to the weighed sum of oligomers from D4 to D13. The daily oral uptake of cyclic siloxanes was calculated, based on published migration and food consumption data. In summary, post-curing of food contact materials made of silicone reduced the exposure of D4 and higher oligomers below the specific migration reference value of 13 mg/kg food.