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Metabolism and Disposition of 2-ethylhexyl-p-methoxycinnamate following Oral Gavage and Dermal Exposure in Harlan Sprague Dawley Rats and B6C3F1/N Mice and in Hepatocytes in vitro

Timothy R. Fennell, James M. Mathews, Rodney W. Snyder, Yan Hong, Scott L. Watson, Sherry R. Black, Barry S. McIntyre, and Suramya Waidyanatha.
Xenobiotica (2017). DOI: https://doi.org/10.1080/00498254.2017.1400129 PMID: 29111853

Publication

Abstract

1. 2-Ethylhexyl-p-methoxycinnamate (EHMC) is commonly used as an ingredient in sunscreens, resulting in potential oral and dermal exposure in humans.
2. Clearance and metabolism of EHMC in hepatocytes and disposition and metabolism of EHMC in rodents following oral (8–800 mg/kg) intravenous (IV) (8 mg/kg) or dermal (0.8–80 mg/kg representing 0.1–10% formulation concentration) exposure to [14C]EHMC were investigated in rats and mice.
3. EHMC was rapidly cleared from rat and mouse hepatocytes (half-life ≤3.16 min) and less rapidly (half-life ≤48 min) from human hepatocytes.
4. [14C]EHMC was extensively absorbed and excreted primarily in urine by 72 h after oral administration to rats (65–80%) and mice (63–72%). Oral doses to rats were excreted to a lesser extent (3–8%) in feces and as CO2 (1–4%). Radioactive residues in tissues were <1% of the dose. There were no sex or species differences in disposition in rats.
5. Following dermal application, 34–42% of an 8–mg/kg dose was absorbed in rats, and 54–62% in mice in 72–h.
6. Among numerous urinary metabolites associated with hydrolysis of the ester, two potential reproductive and developmental toxicants, 2-ethylhexanol and 2-ethylhexanoic acid were produced by metabolism of EHMC.

Figures

Figure 1. HPLC radiochromatograms of hepatocyte incubations with [14C]EHMC (10 μM).

Figure 2. Concentration of radioactivity 72 h following gavage administration in male rat (MR).

Concentration of radioactivity 72 h following gavage administration of [14C]EHMC in male rat (MR). Effect of dose (A) or time after dosing at 8 mg/kg (B).

Figure 3. Concentration of radioactivity in male (MM) and female mice (FM).

Concentration of radioactivity in male (MM) and female mice (FM) administered [14C]EHMC by gavage.

Figure 4. HPLC radiochromatogram of male rat urine.

HPLC radiochromatogram of male rat urine from administration of 800 mg/kg [14C]EHMC demonstrating presence of multiple metabolites, identified by numbers in Table 6. No unchanged EHMC was detected.

Figure 5. Metabolism of EHMC. Metabolites of EHMC (1) identified are named in Table 6.

Figure 6. LC–MS and daughter ion spectra of EHMC metabolites in male rat urine.

The extracted ion chromatogram (m/z 177.0–177.1) of male rat urine administered 800 mg/kg EHMC by gavage is shown in (A). A peak at 18.85 min with an ion at m/z 177.06 was assigned to p-methoxycinnamate (B). A peak at 17.4 min was assigned to p-methoxycinnamic acid glucuronide with an ion at m/z 353.09 (C).

Tables

Table 1. Clearance of EHMC (10 µM) in cryopreserved hepatocytes from rat, mouse and human.

Table 2. Distribution and cumulative excretion of radioactivity up to 72 h following a single oral or IV administration.

Distribution and cumulative excretion of radioactivity up to 72 h following a single oral or IV administration of [14C]EHMC in male and female Harlan Sprague Dawley ratsa.

Table 3. Distribution and cumulative excretion of radioactivity 72 h following a single dermal application.

Distribution and cumulative excretion of radioactivity 72 h following a single dermal application of 8 mg/kg [14C]EHMC in ethanol or lotion in male and female Harlan Sprague Dawley ratsa.

Table 4. Distribution and cumulative excretion of radioactivity following a single oral or IV administration.

Distribution and cumulative excretion of radioactivity up to 72 h following a single oral or IV administration of 8 mg/kg [14C]EHMC in male and female B6C3F1/N micea.

Table 5. Recovery and cumulative excretion of radioactivity 72 h following a single dermal application.

Recovery and cumulative excretion of radioactivity 72 h following a single dermal application of [14C]EHMC to male and female B6C3F1/N micea.

Table 6. Metabolites detected in urine from administration of 800 mg/kg EHMC by gavage to male rats.