Evaluation of subchronic toxicity of the compound of diphenhydramine hydrochloride and caffeine after 28 days of repeated oral administration in Sprague-Dawley rats and beagle dogs

Abstract

This study was designed to evaluate the subchronic toxicity of the compound of diphenhydramine hydrochloride (DH) and caffeine in Sprague-Dawley (SD) rats and beagle dogs. A total of 180 SD rats (15/sex/group) were randomly divided into the compound low-, medium- and high-dose groups (51, 102, 204 mg/kg), DH group (60 mg/kg), caffeine group (144 mg/kg) and the vehicle control group. Sixty beagle dogs (5/sex/group) were randomly divided into the compound low-, medium- and high-dose groups (male: 14.20, 28.30, 56.60 mg/kg, female: 5.66, 14.20, 28.30 mg/kg), DH group (male: 16.60 mg/kg, female: 8.30 mg/kg), caffeine group (male: 40.00 mg/kg, female: 20.00 mg/kg) and the vehicle control group. Rats and dogs were given continuous oral administration for 28 days following a 28-day recovery period. The adverse effects of the compound on rats and beagle dogs mainly included anorexia and liver function impairment. Most adverse effects induced by administration were reversible. Under the experimental conditions, the no-observed-adverse-effect level (NOAEL) of the compound of DH and caffeine was 51 mg/kg/day for SD rats and 28.30 mg/kg/day (male) and 5.66 mg/kg/day (female) for beagle dogs.

Keywords:

• Subchronic toxicity
• diphenhydramine hydrochloride
• caffeine
• rat
• dog

Acknowledgements

The authors would like to thank all technicians who conducted the studies.

Author contributions

Xiaofang Zhang, Jikuai Chen, and Jiangbo Zhu designed this study. Yijun Tian conducted experiments. Haoneng Wang, Bijiang Geng, Jingjing Mao, Tiantian Zhang, Jiqianzhu Zhang, and Yijun Tian collected and analyzed data. Lijun Ren, Lang Yan, and Wenjing Shi wrote the manuscript. Fangyuan Gao, Xiaoyu Dai, Jinfeng Li, Jing Gu, and Yun Chen checked and reanalyzed the data. All the authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was supported by the National Natural Science Foundation of China [Grant No. 82173908, 81803643 and 81872660], the Innovation Action Plan of Shanghai Science and Technology [Grant No. 20140900700], the Social Development Science and Technology research project of Shanghai [Grant No. 21dz1200302 and 20dz1200102], and Major Food Products of the Ministry of Science and Technology of China [Grant No. 2017YFC1600204].