+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Toxicokinetics of bis(2-chloroethoxy)methane following intravenous administration and dermal application in male and female F344/N rats and B6C3F1 mice

, : Toxicokinetics of bis(2-chloroethoxy)methane following intravenous administration and dermal application in male and female F344/N rats and B6C3F1 mice. Toxicology Letters 205(2): 215-226

In the National Toxicology Program's toxicity studies, rats were more sensitive than mice to Bis(2-chloroethoxy)methane (CEM) - induced cardiac toxicity following dermal application to male and female F344/N rats and B6C3F1 mice. Thiodiglycolic acid (TDGA) is a major metabolite of CEM in rats. It has been implicated that chemicals metabolized to TDGA cause cardiac toxicity in humans. Therefore, the toxicokinetics of CEM and TDGA were investigated in male and female F344/N rats and B6C3F1 mice following a single intravenous administration or dermal application of CEM to aid in the interpretation of the toxicity data. Absorption of CEM following dermal application was rapid in both species and genders. Bioavailability following dermal application was low but was higher in rats than in mice with females of both species showing higher bioavailability than males. CEM was rapidly distributed to the heart, thymus, and liver following both routes of administration. Plasma CEM C(max) and AUC(∞) increased proportionally with dose, although at the dermal dose of 400mg/kg in rats and 600mg/kg in mice non-linear kinetics were apparent. Following dermal application, dose-normalized plasma CEM C(max) and AUC(∞) was significantly higher in rats than in mice (p-value<0.0001 for all comparisons except for C(max) in the highest dose groups where p-value=0.053). In rats, dose-normalized plasma CEM C(max) and AUC(∞) was higher in females than in males: however, the difference was significant only at the lowest dose (p-value=0.009 for C(max) and 0.056 for AUC(∞)). Similar to rats, female mice also showed higher C(max) and AUC(∞) in females than in male: the difference was significant only for C(max) at the lowest dose (p-value=0.002). Dose-normalized heart CEM C(max) was higher in rats than in mice and in females than their male counterparts. The liver CEM C(max) was lower compared to that of heart and thymus in both rats and mice following intravenous administration and in rats following dermal application. This is likely due to the rapid metabolism of CEM in the liver as evidenced by the high concentration of TDGA measured in the liver. Dose-normalized plasma and heart TDGA C(max) values were higher in rats compared to mice. In rats, females had higher plasma and heart TDGA C(max) than males; however, there was no gender difference in plasma or heart TDGA C(max) in mice. These findings support the increased sensitivity of rats compared to mice to CEM-induced cardiac toxicity. Data also suggest that, either CEM C(max) or AUC can be used to predict the CEM-induced cardiac toxicity. Although, both plasma and heart TDGA C(max) was consistent with the observed species difference and the gender difference in rats, the gender difference in mice to cardiac toxicity could not be explained based on the TDGA data. This animal study suggests that toxicologically significant concentrations of CEM and TDGA could possibly be achieved in the systemic circulation and/or target tissues in humans as a result of dermal exposure to CEM.


PMID: 21708233

DOI: 10.1016/j.toxlet.2011.06.012

Other references

Serokurov Y.N.; Kalmykov V.D.; Khusam Azam, 2001: Present-day structural framework of the Ladoga-Onega region and its relation to metallogeny. Interpretation of satellite imagery with medium resolution and computer processing of the interpretation results yielded more precise information on the present-day structural framework of the Ladoga-Onega area. Integrated models were used to rapi...

Ullah, R.; Shen, Y.; Zhou, Y-Dong.; Huang, K.; Fu, J-Fen.; Wahab, F.; Shahab, M., 2016: Expression and actions of GnIH and its orthologs in vertebrates: Current status and advanced knowledge. NlmCategory="UNASSIGNED">The physiology of reproduction is very complex and is regulated by multiple factors, including a number of hypothalamic neuropeptides. In last few decades, various neuropeptides have been discovered to be invo...

Gambaudo, S.; Fontanetto, H.; Quaino, O., 1994: Diagnosis of nitrogen fertilization for wheat in the wheat-producing region I. BIBLIOTECA DE CIENCIAS AGRARIAS DEPARTMENTO DE AGRONOMIA [Author] [Third National Congress on Wheat and First National Symposium on Cereals for Autumn-Winter Sowing] III Congreso nacional de trigo y primer simposio nacional de cereales de siembra otono invernal : Pagination varies 47-48

Liu-Jia-Yu; Zhang-Chun-Tian, 2007: A new species of genus Meigenia from China (Diptera, Tachinidae). Meigenia fusciquama sp. nov. (Diptera, Tachinidae) from Jilin and Liaoning, China is described and illustrated. The type specimens are deposited in the Institute of Entomology, Shenyang Normal University, China.

Mims, F.H.; Chang, A.S., 1984: Unwanted sexual experiences of young women. Journal of Psychosocial Nursing and Mental Health Services 22(6): 7-14

Lelong M.P.; Hodge Edwin Stafford, 1954: Spectrographic examination of the occurrence of certain alkali elements in calcite marbles. American Mineralogist 39(7-8): 647-653

Mourer Chauvire Cecile, 1982: The birds of the Quercy phosphorites (upper Eocene to upper Oligocene); paleobiogeographic implications. Geobios, Memoire Special 6: 413-426

Bektas, O.; Uner, A.; Aydin, S.Muruvvet.; Eliacik, E.; Uz, B.; Işık, A.; Haznedaroğlu, I.Celalettin.; Goker, H.; Sayinalp, N.; Aksu, S.; Demiroglu, Hûk.; Ozcebe, O.Ilhami.; Buyukasik, Y., 2016: High frequency of autonomous T-cell proliferation compatible with T-cell large granular lymphocytic leukemia in patients with cytopenia of unknown etiology. Large granular lymphocytic leukemia/lymphoproliferative disorder (LGL-L/LPD) is a heterogeneous neoplastic disease of large granular lymphocytes and is a well-known cause of cytopenias. We aimed to reveal the incidence of LGL-L/LPD in patients wit...

Kolosov, D.; Kelly, S.P., 2013: A role for tricellulin in the regulation of gill epithelium permeability. The apical-most region of cell-to-cell contact in a vertebrate epithelium is the tight junction (TJ) complex. It is composed of bicellular TJs (bTJs) that bridge two adjacent epithelial cells and tricellular TJs (tTJs) that are points of contact b...

Jefferies, E.; Jones, R.W.; Bateman, D.; Ralph, M.A.Lambon., 2005: A semantic contribution to nonword recall? Evidence for intact phonological processes in semantic dementia. Patients with semantic dementia make numerous phonological errors in their immediate serial recall of words that they understand poorly. Previous studies have argued that these errors result from a reduction in the normal contribution made by sema...