Toxicokinetics of chloroethanol in the rat after single oral administration

Grunow, W.; Altmann, Hans

doi:10.1007/bf00347875

Cited by 25 publications

(6 citation statements)

References 29 publications

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“…Thiodiglycolic acid was the major metabolite of (carboxymethyl)cysteine in man, with its sulfoxide present in smaller amounts (18). Chloroethanol undergoes conversion to thiodiglycolic acid and thionyldiacetic acid in the rat (34). Thus, thiodiglycolic acid may undergo oxidation to thionyldiacetic acid in animals receiving AN.…”

Section: Discussionmentioning

confidence: 99%

“…A considerable portion of administered AN is metabolized to jV-acetyl-S-(2cyanoethyl)cysteine, and since this is thought to be specific to AN, this metabolite would represent a suitable marker for exposure to AN (45,46). Many of the products of further metabolism of CEO, such as IV-acetyl-S-(2hydroxyethyl)cysteine, thiodiglycolic acid, and N-acetyl-S-(carboxymethyl)cysteine, are excreted as metabolites of other compounds, including vinyl chloride, ethylene oxide, chloroethanol, and dichloroethane (32,34,47,48). The only metabolite produced exclusively from CEO was Nacetyl-S-(l-cyano-2-hydroxyethyl)cysteine.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Urinary metabolites of [1,2,3-13C]acrylonitrile in rats and mice detected by carbon-13 nuclear magnetic resonance spectroscopy

Fennell

Kedderis²,

Sumner³

1991

Chem. Res. Toxicol.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Urinary metabolites of [1,2,3-13C]acrylonitrile in rats and mice detected by carbon-13 nuclear magnetic resonance spectroscopy

Fennell

Kedderis²,

Sumner³

1991

Chem. Res. Toxicol.

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“…Glutathione conjugates of 2-CE and 2-BE excreted via urine are well characterized (15,27). On the other hand, their fatty acid conjugates formed may accumulate in the tissues and may cause metabolic dysfunctions.…”

Section: Discussionmentioning

confidence: 99%

Hepatic fatty acid conjugation of 2‐chloroethanol and 2‐bromoethanol in rats

Kaphalia¹,

Ansari²

1989

J. Biochem. Toxicol.

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To study the formation of fatty acid conjugates of 2-chloroethanol (2-CE) and 2-bromoethanol (2-BE), rats were administered (by gavage) 50 mg/kg of 2-CE and 2-BE in mineral oil and sacrificed on fifth day of the treatment. Hepatic microsomal lipids were extracted, and the fatty acid esters were separated by preparative thin-layer chromotography. The ester fraction was further purified by reverse-phase, high-performance liquid chromatography and analyzed by ammonia chemical ionization mass spectrometry. Pseudomolecular ions (M + NH4+, base peak) at m/z 336/338, 362/364, and 364/366 in a ratio of 3:1 and 380/382 and 408/410 in a ratio of 1:1 confirmed the in vivo formation of 2-chloroethyl palmitate, 2-chloroethyl oleate, 2-chloroethyl stearate, 2-bromoethyl palmitate, and 2-bromoethyl stearate, respectively. These results demonstrate the formation of fatty acid conjugates of 2-CE and 2-BE in vivo. These fatty acid conjugates may be retained in the body for a longer time and cause toxic manifestations.

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“…showing the presence of TDGA in plasma and tissues following dermal application of CEM in rats and mice of both genders. TDGA is a known metabolite of 2-chloroethanol and 2chloroacetaldehyde (Grunow and Altmann, 1982;Joqueviel et al, 1997). Therefore, it has been postulated that the ether linkage of CEM is cleaved to form 2-chloracetaldehyde which conjugates with glutathione and the glutathione conjugate subsequently undergoes oxidation and metabolism to form TDGA (Black et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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

Waidyanatha¹,

Johnson²,

Hong³

et al. 2011

Toxicology Letters

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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.

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Toxicokinetics of chloroethanol in the rat after single oral administration

Cited by 25 publications

References 29 publications

Urinary metabolites of [1,2,3-13C]acrylonitrile in rats and mice detected by carbon-13 nuclear magnetic resonance spectroscopy

Urinary metabolites of [1,2,3-13C]acrylonitrile in rats and mice detected by carbon-13 nuclear magnetic resonance spectroscopy

Hepatic fatty acid conjugation of 2‐chloroethanol and 2‐bromoethanol in rats

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

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