Study of combined multiple exposure and reproductive / developmental toxicity of 2-ethylhexanoic acid by screening method
- 作者: Masaltsev G.V.1, Khamidulina K.K.2,3, Tarasova E.V.2, Zamkova I.V.4
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隶属关系:
- Federal Scientific Center of Hygiene named after F.F. Erisman of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing
- Russian Register of Potentially Hazardous Chemical and Biological Substances — Branch of the Federal Scientific Center of Hygiene named after F.F. Erisman of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing
- Russian Medical Academy of Continuous Professional Education
- Russian Register of Potentially Hazardous Chemical and Biological Substances – Branch of the Federal Scientific Center of Hygiene named after F.F. Erisman of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing
- 期: 卷 103, 编号 9 (2024)
- 页面: 1037-1043
- 栏目: PREVENTIVE TOXICOLOGY AND HYGIENIC STANDARTIZATION
- ##submission.datePublished##: 15.12.2024
- URL: https://archivog.com/0016-9900/article/view/646072
- DOI: https://doi.org/10.47470/0016-9900-2024-103-9-1037-1043
- EDN: https://elibrary.ru/bqjker
- ID: 646072
如何引用文章
详细
Introduction. According to the normative and methodological documents of the Russian Federation, chemicals introduced into economic activities are subject to mandatory toxicological assessment and hygienic regulation. To substantiate the value of the hygienic standard of 2-ethylhexanoic acid, the production of which is planned in the country, additional test on its reproductive toxicity was required.
The aim of the research was to determine the no-observed adverse effect levels of the 2-ethylhexanoic acid for maternal and reproductive toxicities in combined multiple exposure and the reproduction/developmental toxicity screening test (OECD 422).
Materials and methods. The study was performed in accordance with the requirements of the OECD Test Guideline 422 «Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test».
Results. During the experiment no animal deaths or clinical symptoms of the toxic effect of 2-ethylhexanoic acid were observed at all tested doses (250, 500 and 1000 mg/kg b.w.). The assessment of behavioural responses using the open field method showed no differences in animals from experimental and control group. Histological examination indicated the acid at doses of 500 and 1000 mg/kg b.w. to cause significant changes in bladder (increased sclerosis in the submucosa), lungs (increased proportion of emphysematous altered parenchyma), adrenal gland (increased cell alterations and lipomatous inclusions), thyroid gland (increased loci of interfollicular tissue) in males and females’ rats. The total weight of offspring in the experimental groups was found to be statistically dose-dependent reduced on days 4 and 13 after birth compared with the control.
Limitations. The study had no limitations.
Conclusion. 2-Ethylhexanoic acid has no effect on the reproductive function in experimental animals. Developmental toxicity, expressed in a decrease in the total weight of offspring, was observed at the level of general toxic effects and is not specific. NOAELs were established at the level of 250 mg/kg b.w. for general toxic effect, > 1000 mg/kg b.w. for reprotoxic effect.
Compliance with ethical standards. The study was approved by the bioethical commission of the Federal Scientific Center of Hygiene named after F.F. Erisman.
Contribution:
Khamidulina Kh.Kh. — concept and design of the study, editing, approval of the final version of the article, responsibility for the integrity of all parts of the article;
Tarasova E.V. — concept and design of the study, collection and processing of materials, text writing, editing;
Zamkova I.V. — text writing, editing;
Masaltsev G.V. — experimental work, collection and processing of materials, writing text.
Conflict of interest. The authors declare no conflict of interest.
Acknowledgement. The study was financially supported by Sibur-Khimprom JSC.
Received: May 29, 2024 / Accepted: September 23, 2024 / Published: October 16, 2024
作者简介
Gleb Masaltsev
Federal Scientific Center of Hygiene named after F.F. Erisman of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing
Email: masalcev.gv@fncg.ru
MD, PhD, head of the Toxicology department of the Institute of Hygiene, Toxicology of Pesticides and Chemical Safety, Federal Scientific Center of Hygiene named after F.F. Erisman, Mytishchi, 141014, Russian Federation
e-mail: masalcev.gv@fncg.ru
Khalidya Khamidulina
Russian Register of Potentially Hazardous Chemical and Biological Substances — Branch of the Federal Scientific Center of Hygiene named after F.F. Erisman of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing; Russian Medical Academy of Continuous Professional Education
Email: director@rosreg.info
MD, PhD, DSci., Director of the Russian Register of Potentially Hazardous Chemical and Biological Substances — Branch of Federal Scientific Center of Hygiene named after F.F. Erisman; professor, Head of the Department of Hygiene of the Russian Medical Academy of Continuous Professional Education, Moscow, 121087, Russian Federation
e-mail: director@rosreg.info
Elena Tarasova
Russian Register of Potentially Hazardous Chemical and Biological Substances — Branch of the Federal Scientific Center of Hygiene named after F.F. Erisman of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing
Email: secretary@rosreg.info
MD, PhD, Deputy Director of the Russian Register of Potentially Hazardous Chemical and Biological Substances — Branch of Federal Scientific Center of Hygiene named after F.F. Erisman, Moscow, 121087, Russian Federation
e-mail: secretary@rosreg.info
Irina Zamkova
Russian Register of Potentially Hazardous Chemical and Biological Substances – Branch of the Federal Scientific Center of Hygiene named after F.F. Erisman of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing
编辑信件的主要联系方式.
Email: secretary@rosreg.info
MD, doctor of sanitary and hygienic laboratory research of the Russian Register of Potentially Hazardous Chemical and Biological Substances — Branch of Federal Scientific Center of Hygiene named after F.F. Erisman, Moscow, 121087, Russian Federation
e-mail: secretary@rosreg.info
参考
- GN 1.1.701–98. «Hygienic criteria to substantiate the need to develop MAC and OEL (OAL) for hazardous substances in the air of the working area, atmospheric air in populated areas, water in water bodies»; 1998. (in Russian)
- GOST 12.1.007–76. SSBT. Hazardous substances. Classification and general safety requirements (as amended No. 1,2); 1976. (in Russian)
- Federal Register of Potentially Hazardous Chemical and Biological Substances. Available at: https://rpohv.ru/online/ (in Russian)
- CCOHS RTECS. Canadian Centre Occupational Health and Safety, Registry of Toxic Effects of Chemical Substances; 2023.
- ECHA. European Chemicals Agency’s Dissemination portal with information on chemical substances registered under REACH. Available at: https://echa.europa.eu/home
- GESTIS Substance Database. Database on chemical compounds of the Institute for Occupational Safety and Health of the German Social Accident Insurance Society (IFA). Available at: https://gestis-database.dguv.de/
- GHS Classification Results (J-GHS). National Institute of Technology and Evaluation /NITE/. Available at: https://www.safe.nite.go.jp/english/ghs/all_fy_e.html
- Agency technical report on the classification and labelling of 2-ethylhexanoic acid and its salts, with the exception of those specified elsewhere in this list. Health and Safety Executive Chemicals Regulation Division; 2021.
- Bui L.M., Taubeneck M.W., Commisso J.F., Uriu-Hare J.Y., Faber W.D., Keen C.L. Altered zinc metabolism contributes to the developmental toxicity of 2-ethylhexanoic acid, 2-ethylhexanol and valproic acid. Toxicology. 1998; 126(1): 9–21. https://doi.org/10.1016/s0300-483x(97)00171-6
- Ambroso J.L., Frank E.R., Keller L.H., Trimmer G.W., Waterman S.J. Developmental toxicity assessment of C8 iso acid in CD rats: relevance to embryotoxic aliphatic carboxylic acids. Toxicol. Sci. 1999; 52(2): 240–7. https://doi.org/10.1093/toxsci/52.2.240
- Pennanen S., Tuovinen K., Huuskonen H., Kosma V.M., Komulainen H. Effects of 2-ethylhexanoic acid on reproduction and postnatal development in Wistar rats. Fundam. Appl. Toxicol. 1993; 21(2): 204–12. https://doi.org/10.1006/faat.1993.1090
- Pennanen S., Tuovinen K., Huuskonen H., Komulainen H. The developmental toxicity of 2-ethylhexanoic acid in Wistar rats. Fundam. Appl. Toxicol. 1992; 19(4): 505–11. https://doi.org/10.1016/0272-0590(92)90088-y
- Collins M.D., Scott W.J., Miller S.J., Evans D.A., Nau H. Murine teratology and pharmacokinetics of the enantiomers of sodium 2-ethylhexanoate. Toxicol. Appl. Pharmacol. 1992; 112(2): 257–65. https://doi.org/10.1016/0041-008x(92)90195-x
- Dawson D.A. Additive incidence of developmental malformation for Xenopus embryos exposed to a mixture of ten aliphatic carboxylic acids. Teratology. 1991; 44(5): 531–46. https://doi.org/10.1002/tera.1420440507
- Hauck R.S., Wegner C., Blumtritt P., Fuhrhop J.H., Nau H. Asymmetric synthesis and teratogenic activity of (R)- and (S)-2-ethylhexanoic acid, a metabolite of the plasticizer di-(2-ethylhexyl)phthalate. Life Sci. 1990; 46(7): 513–8. https://doi.org/10.1016/0024-3205(90)90007-e
- Hendrickx A.G., Peterson P.E., Tyl R.W., Fisher L.C., Fosnight L.J., Kubena M.F., et al. Assessment of the developmental toxicity of 2-ethylhexanoic acid in rats and rabbits. Fundam. Appl. Toxicol. 1993; 20(2): 199–209. https://doi.org/10.1006/faat.1993.1027
- Narotsky M.G., Francis E.Z., Kavlock R.J. Developmental toxicity and structure-activity relationships of aliphatic acids, including dose-response assessment of valproic acid in mice and rats. Fundam. Appl. Toxicol. 1994; 22(2): 251–65. https://doi.org/10.1006/faat.1994.1029
- Ritter E.J., Scott W.J. Jr., Randall J.L., Ritter J.M. Teratogenicity of di(2-ethylhexyl) phthalate, 2-ethylhexanol, 2-ethylhexanoic acid, and valproic acid, and potentiation by caffeine. Teratology. 1987; 35(1): 41–6. https://doi.org/10.1002/tera.1420350107
- Svechnikova I., Svechnikov K., Söder O. The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats. J. Endocrinol. 2007; 194(3): 603–9. https://doi.org/10.1677/JOE-07-0238
- Assessment report. Reconsideration of Nine Chemicals Listed under Proposition 65 as Known to Cause Reproductive Toxicity. Office of Environmental Health Hazard Assessment California Environmental Protection Agency; 2013. Available at: https://oehha.ca.gov/media/downloads/proposition-65/chemicals/2013septdartichid.pdf
- Khamidulina Kh.Kh., Tarasova E.V., Zamkova I.V., Nazarenko A.K. Substantiation of maximum allowable concentration of 2-ethylhexanoic acid in the air of the working area. Toksikologicheskii vestnik. 2024; 32(2): 72–86. https://doi.org/10.47470/0869-7922-2024-32-2-72-86 https://elibrary.ru/fvzibo (in Russian)
- GOST 34555–2019. Methods of testing the chemicals of human hazard. Determination of repeated/multiple dose toxicity with simultaneous assessment of reproduction/developmental toxicity by screening method. Moscow; 2019. (in Russian)
- Guide R 1.2.3156–13. Assessment of the toxicity and hazard of chemicals and their mixtures for human health. Moscow; 2014. (in Russian)
- Khalafyan A.A. STATISTICA 6. Statistical Data Analysis [STATISTICA 6. Statisticheskii analiz dannykh]. Moscow: Binom Press; 2007. (in Russian)
- Corder G.W., Foreman D.I. Nonparametric Statistics: A Step-by-Step Approach. Hoboken: John Wiley & Sons; 2014.
- Agresti A. Categorical Data Analysis. Hoboken: John Wiley & Sons; 2003.
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