Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

N-methylformamide induces multiple organ toxicity in Fischer 344 rats

  • Mi Ju Lee (Inhalation Toxicity Research Center, Chemicals Toxicity Research Bureau, Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency) ;
  • Hyo‑Geun Cha (Inhalation Toxicity Research Center, Chemicals Toxicity Research Bureau, Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency) ;
  • Ka Young Park (Inhalation Toxicity Research Center, Chemicals Toxicity Research Bureau, Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency) ;
  • Yong‑Soon Kim (Inhalation Toxicity Research Center, Chemicals Toxicity Research Bureau, Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency) ;
  • Byeongwoo Ahn (Department of Veterinary Pathology, College of Veterinary Medicine, Chungbuk National University)
  • Received : 2022.09.13
  • Accepted : 2022.12.15
  • Published : 2023.04.15
⟨ Previous Next ⟩

Abstract

N-Methylformamide (NMF) is a widely used chemical (CAS No.: 123-39-7) in several industries and its usage is continuously increasing. However, studies for NMF have been focused on hepatotoxicity from now. Its toxicity profile has not yet been established owing to limited toxicity data. Therefore, we evaluated systemic toxicity via NMF inhalation. We exposed 0, 30, 100, and 300 ppm NMF to Fischer 344 rats for 6 h/day, 5 days a week for 2 weeks. Clinical signs, body weights, food consumption, hematologic parameters, serum chemistry measurements, organ weights, necropsy, and histopathology were performed. Two females exposed to 300 ppm NMF died during exposure period. Decrease of food consumption and body weight in both sexes exposed to 300 ppm in females exposed to 100 ppm were noted during exposure period. Increased RBC and HGB were noted in females exposed to 300 ppm. A decrease in the levels of ALP and K and increase in the levels of TCHO and Na were observed in both sexes exposed to 300 and 100 ppm. Increased levels of ALT, AST, BUN and decreased levels of TP, ALB, Ca were observed in females exposed to 300 and 100 ppm. The relative liver weight was elevated in both sexes exposed to 300 and 100 ppm NMF. Hypertrophy in the liver and submandibular glands and nasal cavity injuries were noted in both sexes exposed to 300 and 100 ppm NMF. Tubular basophilia of the kidneys were noted in females exposed to 300 ppm NMF. We revealed that NMF affect several organs including the kidneys not only the liver and NMF-related toxicity is predominant in female rats. These results could contribute to the development of NMF toxicity profile and may help in developing strategies for the control of occupational environmental hazards related to NMF.

Keywords

Acknowledgement

We are grateful to all researchers of Occupational Safety and Health Research Institute who contributed to this study.

References

  1. Wang V-S, Shih T-S, Cheng C-C, Chang H-Y, Lai J-S, Lin C-C (2004) Evaluation of current biological exposure index for occupational N, N-dimethylformamide exposure from synthetic leather workers. J Occup Environ Med 46:729-736. https://doi.org/10.1097/01.jom.0000131795.88947.45
  2. Yamasaki M, Akagi S, Nogaoka K, Burgess LJ, Shiwaku K (2016) The significance of using the biomarkers of N, N-dimethylformamide for improvement of health risk management in the artificial leather industry. Shimane J Med Sci 32:51-59
  3. IARC (2018) IARC Monographs on the evaluation of carcinogenic risks to humans, volume 115. https://publications.iarc.fr/563. Accessed 8 June 2021
  4. Transparency Market Research. N-methylformamide market: global industry analysis, size, share, growth, trend, and forecast, 2019-2027. https://www.transparencymarketresearch.com/nmethylformamide-market.html. Accessed 12 Apr 2021
  5. ECHA. N-methylformamide. https://echa.europa.eu/registration-dossier/-/registered-dossier/12311/2/1. Accessed 12 Apr 2021
  6. Pubchem. N-Nemthylformamide. National Institutes of Health (NIH). https://pubchem.ncbi.nlm.nih.gov/compound/31254. Accessed 2 July 2022
  7. Kennedy GL Jr, Ferenz RL, Burgess BA, Stula EF (1990) 2-week inhalation study of N-monomethylformamide in rats. Fundam Appl Toxicol 14:810-816. https://doi.org/10.1016/0272-0590(90)90305-4
  8. Tulip K, Timbrell JA (1988) Comparative hepatotoxicity and metabolism of N-methylformamide in rats and mice. Arch Toxicol 62:167-176. https://doi.org/10.1007/BF00570135
  9. Van den Bulcke M, Rosseel MT, Wijnants P, Buylaert W, Belpaire FM (1994) Metabolism and hepatotoxicity of N, N-dimethylformamide, N-hydroxymethyl-N-methylformamide, and N-methylformamide in the rat. Arch Toxicol 68:291-295. https://doi.org/10.1007/s002040050071
  10. Rickard LB, Driscoll CD, Kennedy GL Jr, Staples RE, Valentine R (1995) Developmental toxicity of inhalaed N-methylformamide in the rat. Fundam Appl Toxicol 28:167-176. https://doi.org/10.1006/faat.1995.1157
  11. Hyland R, Gescher A, Thummel K, Schiller C, Jheeta P, Mynett K, Smith AW, Mraz J (1992) Metabolic oxidation and toxification of N-methylformamide catalyzed by the cytochrome P450 isoenzyme CYP2E1. Mol Pharmacol 41:259-266
  12. Gopinath C, Prentice DE, Lewis DJ (1987) Atlas of experimental toxicological pathology. MTP Press Limited, Lancaster
  13. Everd NE, Snyder PW, Bailey KL, Bolon B, Creasy DM, Foley GL, Rosol TJ, Sellers T (2013) Interpreting stress responses during routine toxicity studies: a review of the biology, impact, and assessment. Toxicol Pathol 41:560-614. https://doi.org/10.1177/0192623312466452
  14. Fulda S, Gorman AM, Hori O, Samali A (2010) Cellular stress responses-cell survival and cell death. Int J Cell Biol 2010:214074. https://doi.org/10.1155/2010/214074
  15. Rehm S, White TE, Zahalka EA, Stanislaus DJ, Boyce RW, Wier PJ (2008) Effects of food restriction on testis and accessory sex glands in maturing rats. Toxicol Pathol 36:687-694. https://doi.org/10.1177/0192623308320275
  16. Blackburn GL, Bistrian BR, Hoag C (1977) Hair loss with rapid weight loss. Arch Dermatol 113:234. https://doi.org/10.1001/jama.1976.03270030012010
  17. Malkud S (2015) Telogen effluvium: a review. J Clin Diagn Res 9:WE01-WE03. https://doi.org/10.7860/JCDR/2015/15219.6492