Safety evaluation of dufulin racemate and its R(S)-enantiomers in rats based on dose-effect relationship, time-effect relationship, and lipidomics. (September 2021)

• Record Type: Journal Article
• Authors: Chen, Huaguo; Zhou, Xin; Yang, Qin
• Is Part Of: Toxicology. Volume 461(2021)
• Publication Date: 2021-09
• Subjects: rac-DFL dufulin racemate -- (R)-DFL (R)-enantiomers of dufulin -- (S)-DFL (S)-enantiomers of dufulin -- UHPLC-MS/MS ultra-high performance liquid chromatography-mass spectrum-mass spectrum -- ALT alanine aminotransferase -- AST aspartate aminotransferase -- TBil total bilirubin -- DBil direct bilirubin -- IBil indirect bilirubin -- BUN serum urea -- Scr serum creatinine -- β2-MG β2-microglobulin -- UA uric acid -- QC quality control -- MTBE methyl tert-butyl ether -- PCA principal component analysis -- PLS-DA supervised least squares discriminant analysis -- OPLS-DA orthogonal partial least squares discriminant analysis; Dufulin -- Time-effect relationship -- Dose-response relationship -- Lipidomics -- Safety evaluation; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2021.152895
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: In the present study, the dose-effect and time-effect relationships of Dufulin racemate ( rac - DFL ) and its R(S) -enantiomers in rats were investigated after oral administration to evaluate their safety. A total of six doses (2.5, 5.0, 10.0, 20.0, 50.0, and 100.0 mg/kg) were administered and seven time-intervals (1 h, 3 h, 1 d, 3 d, 5 d, 7 d, and 14 d) were considered to observe the effects of rac - DFL, (R) - DFL, and (S) - DFL on general behavioral characteristics, liver and kidney functions, pathological changes, and lipid metabolism in rats. The results showed that the rats in each group exhibited a good mental state, agile activity, smooth and shiny fur, and normal diet. Viscera indices of heart, liver, spleen, lung, and kidney were 5.10–5.56, 4.15–4.59, 0.24–0.28, 6.08–6.48, and 11.02–11.98 mg/g for dose-effect relationships, and 5.01–5.94, 4.11–4.79, 0.24–0.30, 6.00–6.87, and 11.02–11.99 mg/g for time-effect relationships, respectively. Values of ALT, AST, TBil, DBil, IBil, BUN, Scr, β2-MG, and UA were 33.02–38.93 U/L, 108.17–126.53 U/L, 16.22–17.94 μmol/L, 5.75–8.12 μmol/L, 9.50–10.94 μmol/L, 4.03–5.85 mmol/L, 19.42–21.61 μmol/L, 48.16–52.73 mg/L, and 68.51–78.65 μmol/L, respectively. The statistical results showed that there were no significant differences in organ indices as well as liver and kidney function indices among different groups. In terms of pathological morphology, liver and kidney tissue sections of different groups of rats demonstrated normalcy. Rac - DFL, (R) - DFL, and (S) - DFL in the range of 2.5–100.0 mg/kg exerted no significant effect on lipid metabolism. Compared with the blank group, 35, 55, and 14 differential lipids were screened from rac - DFL, (S) - DFL, and (R)- DFL groups, respectively. These lipid changes completely returned to normalcy within 3 h. There were no significant differences at 1, 3, 5, 7, and 14 d after gavage. These results will aid further evaluation of the safety of dufulin and for provision of scientific evidence for its application as a pesticide.