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

IF 3 4区医学 Q1 MEDICINE, LEGAL Regulatory Toxicology and Pharmacology Pub Date : 2024-09-26 DOI:10.1016/j.yrtph.2024.105712

Akira Kawashima, Kaoru Inoue

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Abstract

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 Unpublished individual data from the oral TMAH developmental and reproductive toxicity (DART) screening study were also obtained; no effect on heart weight was observed.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.

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重新评估四甲基氢氧化铵 28 天口服重复剂量毒性研究中雄性大鼠心脏重量减少的情况。

我们最近对四甲基氢氧化铵（TMAH）进行了详细的危害评估，该物质是《日本化学物质控制法》规定的重点化学物质。在评估过程中，我们发现在为期 28 天的大鼠口服重复剂量毒性研究中，经处理的雄性组心脏重量有所减轻，对此存在争议。在这项研究以及四甲基氯化铵（TMAC）或邻苯二甲酸氢四甲基铵（TMAHP）的雌雄口服毒性研究中，均未观察到这一结果。此外，还获得了口服 TMAH 发育和生殖毒性（DART）筛选研究中未公布的个体数据；未观察到对心脏重量的影响。此外，还从日本现有化学物质数据库（JECDB）中获取了六项为期 28 天的口服毒性研究的大鼠心脏重量背景数据，这些研究是在与 TMAH 研究相同的设施、年份、品系、年龄和饲养者中进行的。这些调查表明，在 28 天的毒性研究中，经处理的雄性动物的心脏重量在统计意义上显著降低，这可能是由于心脏重量较重的个体偶然偏向对照雄性动物组，而不是由于 TMAH 处理造成的。因此，值得在毒性研究中纳入尽可能多的相关数据，以证实或反驳意外发现。

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来源期刊

Regulatory Toxicology and Pharmacology 医学-毒理学

CiteScore

6.70

自引率

8.80%

发文量

147

审稿时长

58 days

期刊介绍： Regulatory Toxicology and Pharmacology publishes peer reviewed articles that involve the generation, evaluation, and interpretation of experimental animal and human data that are of direct importance and relevance for regulatory authorities with respect to toxicological and pharmacological regulations in society. All peer-reviewed articles that are published should be devoted to improve the protection of human health and environment. Reviews and discussions are welcomed that address legal and/or regulatory decisions with respect to risk assessment and management of toxicological and pharmacological compounds on a scientific basis. It addresses an international readership of scientists, risk assessors and managers, and other professionals active in the field of human and environmental health. Types of peer-reviewed articles published: -Original research articles of relevance for regulatory aspects covering aspects including, but not limited to: 1.Factors influencing human sensitivity 2.Exposure science related to risk assessment 3.Alternative toxicological test methods 4.Frameworks for evaluation and integration of data in regulatory evaluations 5.Harmonization across regulatory agencies 6.Read-across methods and evaluations -Contemporary Reviews on policy related Research issues -Letters to the Editor -Guest Editorials (by Invitation)