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Disposition of Tris(4-chlorophenyl)methanol and Tris(4-chlorophenyl)methane in Male and Female Harlan Sprague Dawley Rats and B6C3F1/N Mice Following Oral and Intravenous Administration

Natasha Catlin, Suramya Waidyanatha, Sherry R. Black, James Mathews, Rodney W Snyder, Purvi Patel, Scott Watson, and Timothy R Fennell.
Xenobiotica (2018) DOI: https://doi.org/10.1080/00498254.2018.1463475 PMID: 29659319

Publication

Abstract

1. Tris(4-chlorophenyl)methane (TCPME) and Tris(4-chlorophenyl)methanol (TCPMOH) have been detected in various biota and human tissues.
2. The current studies were undertaken to investigate the disposition and metabolism of TCPME and TCPMOH in rats and mice.
3. [14C]TCPME was well absorbed (≥ 66%) in male rats and mice following a single oral administration of 1, 10, or 100 mg/kg. The excretion of [14C]TCPME-derived radioactivity in urine (≤ 2.5%) and feces (≤18%) was low. The administered dose was retained in tissues (≥ 64%) with adipose containing the highest concentrations. The metabolism of TCPME was minimal. The disposition and metabolism of [14C]TCPME in females was similar to males.
4. The time to reach maximum concentration was ≤7 h, the plasma elimination half-life was ≥ 31 h, and the bioavailability was ≥ 82% following a 10 mg/kg oral dose of [14C]TCPME in male rats and mice.
5. The disposition of [14C]TCPMOH was similar to that of [14C]TCPME.
6. Following an intravenous administration of [14C]TCPME or [14C]TCPMOH in male rats and mice, the pattern of disposition was similar to that of oral administration.
7. In conclusion, both TCPME and TCPMOH are readily absorbed and highly bioavailable following a single oral administration pointing to importance of assessing the toxicity of these chemicals.

Figures

Figure 1. Tissue to blood ratios (TBR) estimated in male Harlan Sprague Dawley rats (TCPME).

Tissue to blood ratios (TBR) estimated in male Harlan Sprague Dawley rats 72 h following a single oral administration of [14C]TCPME. Data (mean ± SEM) for selected tissues are shown.

Figure 2. Tissue to blood ratios (TBR) estimated in male B6C3F1/N mice (TCPME).

Tissue to blood ratios (TBR) estimated in male B6C3F1/N mice 72 h following a single oral administration of [14C]TCPME. Data (mean ± SEM) for selected tissues are shown.

Figure 3. Tissue to blood ratios (TBR) estimated in male Harlan Sprague Dawley rats and B6C3F1/N mice (TCPMOH).

Tissue to blood ratios (TBR) estimated in male Harlan Sprague Dawley rats and B6C3F1/N mice 72 h following a single oral or intravenous administration of 10 mg/kg [14C]TCPMOH. Data (mean ± SEM) for selected tissues are shown.

Figure 4. HPLC radiochromatogram of A) urine (0-8 h) and B) bile (0-12 h) (72 h) following a single oral administration.

HPLC radiochromatogram of A) urine (0-8 h) and B) bile (0-12 h) (72 h) following a single oral administration of 100 mg/kg [14C]TCPME to male Harlan Sprague Dawley rats.

Figure 5. HPLC radiochromatogram of adipose 72 h following a single oral administration.

HPLC radiochromatogram of adipose 72 h following a single oral administration of A) 100 mg/kg [14C]TCPME B) 10 mg/kg [14C]TCPMOH to male rats.

Figure 6. Plot of total radioactivity in plasma versus time following a single IV or oral administration (TCPME, Rats).

Plot of total radioactivity in plasma versus time following a single IV (A) or oral (B) administration of 10 mg/kg [14C]TCPME to Male Harlan Sprague Dawley rats. Intravenous data was fit to a twocompartment model with bolus input and 1/y*y weighting. Gavage data were fit to a two-compartment model with extravascular input.

Figure 7. Plot of total radioactivity in plasma versus time following a single IV or oral administration (TCPME, Mice).

Plot of total radioactivity in plasma versus time following a single IV (A) or oral (B) administration of 10 mg/kg [14C]TCPME to male B6C3F1/N mice. Intravenous data was fit to a two-compartment model with bolus input and 1/y*y weighting. Gavage data were fit to a two-compartment model with extravascular input.

Figure 8. Plot of TCMPE radioactivity in plasma versus time following IV (A) or oral (B) administration.

Plot of TCMPE radioactivity in plasma versus time following IV (A) or oral (B) administration of 10 mg/kg [14C]TCPME to Male B6C3F1/N mice. Intravenous data was fit to a two-compartment model with bolus input and 1/y*y weighting. Gavage data were fit to a two-compartment model with extravascular input.

Tables

Table 1. Excretion of Radioactivity 72 Hours following Oral or Intravenous Administration (TCPME, Rats).

Excretion of Radioactivity 72 Hours following Oral or Intravenous Administration of [14C]TCPME to Male and Female Harlan Sprague Dawley Rats

Table 2. Excretion of Radioactivity 72 Hours following Oral or Intravenous Administration (TCPME, Mice).

Excretion of Radioactivity 72 Hours following Oral or Intravenous Administration of [14C]TCPME to Male and Female B6C3F1/N Mice

Table 3. Excretion of Radioactivity 72 Hours following Oral or Intravenous Administration (TCPMOH, Rats and Mice).

Excretion of Radioactivity 72 Hours following Oral or Intravenous Administration of [14C]TCPMOH (10 mg/kg) to Male Harlan Sprague Dawley Rats and B6C3F1/N Mice.

Table 4. Plasma toxicokinetic parameters following a single oral or intravenous administration (TCPME, Rats and Mice).

Plasma toxicokinetic parameters following a single oral or intravenous administration of 10 mg/kg [14C]TCPME to male Harlan Sprague Dawley Rats and B6C3F1/N mice.

Supplemental Materials

Supplemental Material