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The potential of tris (2-ethylhexyl) trimellitate (TOTM) to induce testicular mal-development(TMD) has been studied in the rat and compared with the positive controls, di- (2-ethylhexyl) phthalate (DEHP) and its active metabolite, mono-(2-ethylhexyl) phthalate (MEHP). The effects of TOTM on the expression of genes in pathways involved in steroidogenesis and testes development previously shown to be involved in the induction of TMD by certain phthalate esters were studied using transcriptional profiling techniques on RNA extracted from the testes of rats exposed in utero to either TOTM or the positive controls.
A second study examined foetal testis testosterone production, pregnant rat dams being dosed daily from gestation day (GD) 14 to GD 18 followed, approximately 2 hours after dosing on GD 18, examination of testis testosterone production measured ex vivo.

Additional information

In a study of trancriptional profiling, rats were exposed to TOTM in utero by the administration of daily oral gavage doses to pregnant dams between gestational day 12 and 19. The foetal testes were obtained by micro-dissection and prepared to facilitate the isolation of RNA, which was subsequently analysed using whole rat genome microarrays. The study was focussed on assessment of effects in pathways relevant to rat testicular mal-development (TMD). The effects of TOTM were compared with those of diethylhexyl phthalate (DEHP) and mono-(2-ethylhexyl) phthalate (MEHP), an active metabolite of DEHP, both of which were used as positive controls.

MEHP & DEHP (500 mg/Kg) caused a repression of genes in TMD pathways involved in cholesterol synthesis and transport (HMGCS, HMGCR, STAR, SCARB1, FDFT1, FDPS), Steroidogenesis (Cyp11a, HSD3B1, SC4MOL) and testes development (INSL3, INHA)

TOTM did not cause significant repression of genes in TMD pathway.

In conclusion, it is highly unlikely that TOTM will cause testicular mal-development in the rat under these treatment conditions.

 

In a second study, examining foetal testis testosterone production, pregnant rat dams were dosed daily by oral gavage from gestation day (GD) 14 to GD 18 with 0 (corn oil - vehicle control at 2.5 ml/kg) or with TOTM at 750 mg/kg/day. Approximately 2 hours after dosing on GD 18, dams were killed by decapitation and exsanguination, and the foetuses removed and killed by decapitation. All foetal necropsies were conducted within a 2 hour period to ensure that a similar developmental period was sampled.Testis testosterone production (T Prod) was measured ex vivo from 3 males per litter from 3 litters. A subsequent dose-response study followed the same regime with TOTM administered at dose levels of 0, 250, 500 and 1000 mg/kg/day.

TOTM did not reduce testis testosterone production and was therefore regarded as being negative in the assay and unlikely to produce adverse developmental outcomes in male offspring.