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A 90-Day Inhalation Toxicity Study of Ethyl Formate in Rats

  • Lee, Mi Ju (Department of Pathology, Inhalation Toxicity Research Center, Chemicals Toxicity Research Bureau, Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency) ;
  • Kim, Hyeon-Yeong (Department of Pathology, Inhalation Toxicity Research Center, Chemicals Toxicity Research Bureau, Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency)
  • Received : 2017.07.19
  • Accepted : 2017.08.29
  • Published : 2017.10.15

Abstract

Ethyl formate, a volatile solvent, has insecticidal and fungicidal properties and is suggested as a potential fumigant for stored crop and fruit. Its primary contact route is through the respiratory tract; however, reliable repeated toxicological studies focusing on the inhalation route have not been published to date. Therefore, the present study was conducted to investigate the safety of a 90-day repeated inhalation exposure in rats. Forty male and 40 female rats were exposed to ethyl formate vapor via inhalation at concentrations of 0, 66, 330, and 1,320 ppm for 6 hr/day, 5 days a week for 13 weeks. Clinical signs, body weights, food consumption, urinalysis, hematologic parameters, serum chemistry measurements, organ weights, necropsy, and histopathological findings were compared between the control and ethyl formate-exposed groups. Locomotor activity decreased during exposure and recovered afterward in male and female rats exposed to 1,320 ppm ethyl formate. Body weight and food consumption continuously decreased in both sexes exposed to 1,320 ppm ethyl formate from week 1 or 3 compared with the control values. The increases in adrenal weight and decreases in thymus weight were noted in both sexes exposed to ethyl formate at 1,320 ppm. Degeneration, squamous metaplasia of olfactory epithelium in the nasopharyngeal tissue, or both were noted in the male and female rats at 1,320 ppm and female rats at 330 ppm ethyl formate. Taken together, our results indicate that ethyl formate-induced changes were not observed in male and female rats at 330 and 66 ppm, respectively. This indicates that exposure to ethyl formate at concentrations below 66 ppm for 90 days is relatively safe in rats. This is the first report of a full-scale repeated inhalation toxicity assessment in rats and could contribute to controlling occupational environmental hazards related to ethyl formate.

Keywords

References

  1. Desmarchelier, J.M., Johnston, F.M. and Vu, L.T. (1999) Ethyl formate, formic acid and ethanol in air, wheat, barley and sultanas: analysis of natural levels and fumigant residues. Pest Manag. Sci., 55, 815-824. https://doi.org/10.1002/(SICI)1096-9063(199908)55:8<815::AID-PS22>3.0.CO;2-4
  2. Haritos, V.S., Damcevski, K.A. and Dojchinov, G. (2003) Toxicological and regulatory information supporting the registration of $VAPORMATE^{TM}$ as a grain fumigant for farm storages in Stored Grain in Australia 2003: Proceedings of the Australian Postharvest Technical Conference, Canberra, 25-27 June 2003 (Wright, E.J., Webb, M.C. and Highley, E. Eds.). pp. 193-198.
  3. Simpson, T., Bikoba, V. and Mitcham, J.E. (2004) Effects of ethyl formate on fruit quality and target pest mortality for harvested strawberries. Postharvest Biol. Technol., 34, 313-319. https://doi.org/10.1016/j.postharvbio.2004.05.015
  4. Bell, C.H. (2000) Fumigation in the 21st century. Crop Prot., 19, 563-569. https://doi.org/10.1016/S0261-2194(00)00073-9
  5. Haritos, S.V., Damcevski, A.K. and Dojchinov, G. (2006) Improved efficacy of ethyl formate against stored grain insects by combination with carbon dioxide in a 'dynamic' application. Pest Manag. Sci., 62, 325-333. https://doi.org/10.1002/ps.1167
  6. Ciesla, Y., Rouzes, R., Fritsch, J. and Ducom, P. (2008) Efficacy of a new grain fumigant: ethyl formate/allyl isothiocyanate for the control of two stored grain beetles, the rice weevil Sitophilus oryzae L. and the granary weevil Sitophilus granarius L. IOBC/WPRS Bull., 40, 325-334.
  7. Yang, J., Park, Y., Hyun, I.-H., Kim, G.-H., Kim, B.-S., Lee, B.-H. and Ren, Y. (2016) A combination treatment using ethyl formate and phosphine to control planococcus citri (Hemiptera: Pseudococcidae) on pineapples. J. Econ. Entomol., 109, 2355-2363. https://doi.org/10.1093/jee/tow222
  8. Sah, H. (2000) Ethyl formate - alternative dispersed solvent useful in preparing PLGA microspheres. Int. J. Pharm., 195, 103-113. https://doi.org/10.1016/S0378-5173(99)00379-8
  9. Health Council of the Netherlands: Committee on Updating of Occupational Exposure Limits (2002) Health-based Reassessment of Administrative Occupational Exposure Limits; Ethyl formate, Health Council of the Netherlands, The Hague, publication no. 2000/15O.
  10. Occupational Safety and Health Administration. Ethyl Formate. [cited 2017 Jun 23]. Available from: https://www.osha.gov/dts/chemicalsampling/data/CH_240500.html/.
  11. Ministry of Employment and Labor. Act No. 2016-41, chemical hazard information and workplace exposure limits. Available from: http://www.moel.go.kr/view.jsp?cate=3&sec=1&smenu=4&mode=view&bbs_cd=116&state=A&seq=1471867552025/.
  12. Ku, H.R. (2000) An overview of setting occupational exposure limits (OELs) for pharmaceuticals. Chem. Health Safety, 7, 34-37.
  13. European Centre for Ecotoxicology and Toxicology of Chemicals (ECETC) (2006) Technical Report No. 101: Guidance for setting occupational exposure limits: Emphasis on datapoor substances, ISSN-0773-8072-101.
  14. Stoner, D.G., Shimkin, B.M., Kniazeff, J.A., Weisburger, H.J., Weisburger, K.E. and Gori, B.G. (1973) Test for carcinogenicity of food additives and chemotherapeutic agents by the pulmonary tumor response in strain A mice. Cancer Res., 33, 3069-3085.
  15. Hagan, E.C., Henson, W.H., Fitzhugh, O.G., Jenner, P.M., Jones, W.I., Taylor, J.M., Long, E.L., Nelson, A.A. and Brouwer, J.B. (1967) Food flavourings and compounds of related structure. II. Subacute and chronic toxicity. Food Cosmet. Toxicol., 5, 141-157. https://doi.org/10.1016/S0015-6264(67)82961-4
  16. Everds, E.N., Snyder, W.P., Bailey, L.K., Bolon, B. Creasy, M.D., Foley, L.G., Rosol, J.T. and 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
  17. Hall, R.L. (2013) Principles of clinical pathology in Toxicologic Pathology: Nonclinical Safety Assessment (Sahota, P.S., Popp, J.A., Hardisty, J.F. and Gopinatph, C. Eds.). CRC Press, India, pp. 133-173.
  18. Hall, R.L. and Everds, N.E. (2014) Principles of clinical pathology for toxicology studies in Hayes' Principles and Methods of Toxicology (6th edition) (Hayes, A.W. and Kruger, C.L. Eds.). CRC Press, New York, pp. 1305-1344.
  19. Kwon, S., Yang, Y.-S., Yang, H.-S., Lee, J., Kang, M.-S., Lee, B.-S., Lee, K. and Song, C.-W. (2012) Nasal and pulmonary toxicity of titanium dioxide nanoparticles in rats. Toxicol. Res., 28, 217-224. https://doi.org/10.5487/TR.2012.28.4.217

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