Re-evaluation of the reduced heart weights in male rats in a 28-day oral repeated-dose toxicity study of tetramethylammonium hydroxide.

We recently conducted a detailed hazard assessment of tetramethylammonium hydroxide (TMAH), a priority chemical substance under the Japan Chemical Substances Control Law. During this assessment, there was debate regarding the reduced heart weight observed in the treated male groups in the 28-day rat oral repeated-dose toxicity study. This finding was not observed in females in this study and in both sexes of oral toxicity studies for tetramethylammonium chloride (TMAC) or tetramethylammonium hydrogen phthalate (TMAHP). Unpublished individual data from the oral TMAH developmental and reproductive toxicity (DART) screening study were also obtained; no effect on heart weight was observed. In addition, background data on rat heart weight from six 28-day oral toxicity studies conducted in the same facility, year, strain, age, and breeder as the TMAH study were obtained from the Japan Existing Chemical Substances Database (JECDB). These investigations suggest that the statistically significant lower heart weight in the treated males in the 28-day toxicity study is likely caused by an incidental skewing of individuals with heavier heart weights toward control male groups and is not due to TMAH treatment. Thus, it is worthwhile to include as much relevant data as possible to confirm or refute unexpected findings in toxicity studies.