More than 90% of a single oral dose of 80 mg of [carboxy-14C]phenylacetic acid administered to each of three healthy volunteers and two patients with phenylketouria was excreted in the urine within 24 h as the glutamine conjugate (In a third patient with phenylketouria in this study, 12% of the dose was excreted as the glutamine conjugate, but this was attributed to incomplete collection of urine.) (James et al., 1973). Two male volunteers excreted 98% of an oral dose of 1 mg/kg bw of [carboxy-14C]phenylacetic acid in their urine within 24 h (James et al., 1972), with > 90% of the dose recovered as the glutamine conjugate. The results of studies with radiolabelled phenylacetic acid indicate that it is rapidly absorbed and quantitatively excreted within 24 h.
If evidence can be supplied to show that an ester is readily hydrolysed in the body to constituents whose metabolic fate and biological actions are fully understood, further toxicological studies may not be necessary. Consequently, artificial gastro-intestinal juices have been used to study the hydrolysis of esters (Longland et al., 1977). Before absorption in vivo, the esters and acetals in this group can be reasonably predicted to undergo hydrolysis (Williams, 1959) to yield phenethyl alcohol, phenoxyethyl alcohol, phenylacetaldehyde, phenylacetic acid and phenoxyacetic acid. Phenethyl acetate (No. 989), methyl phenylacetate (No. 1008), ethyl phenylacetate (No. 1009), isopropyl phenylacetate (No. 1011), isoamyl phenylacetate (No. 1014) and citronellyl phenylacetate (No. 1021) were rapidly hydrolysed in vitroin simulated gastric juice and pancreatic juice (Nos 989, 1008 and 1009) (Longland et al., 1977) or in a buffered solution of pancreatin (Nos 1008, 1011, 1014 and 1021) (Grundschober, 1977) to the corresponding phenethyl derivatives. Phenethyl acetate (No. 989), ethyl phenylacetate (No. 1009) and isoamyl phenylacetate (No. 1014) were not hydrolysed by partially purified human plasma arylesterase (Augustinsson & Ekedahl, 1962).
A hydroxy or hydroxyl group is the entity with the formula OH
Phenethyl alcohol (No. 987), phenylacetaldehyde (No. 1002), phenylacetic acid (No. 1007), ethyl phenylacetate (No. 1009), isobutyl phenylacetate (No. 1013), isoamyl phenylacetate (No. 1014) and -tolylacetaldehyde (No. 1023) have been tested for their ability to induce reverse mutation in various strains of (e.g., TA98, TA100, TA1535, TA1537 and TA1538) in the presence or absence of an exogenous metabolic activation system. None of the compounds was mutagenic when tested at concentrations up to 5000 µg/ml or 50 mg/plate (Oda et al., 1979; Florin et al., 1980; Rapson et al., 1980; Ishidate et al., 1984; Heck et al., 1989; Kato et al., 1989; Fujita et al., 1994). No reverse mutation was seen when various strains of (TA98, TA100, TA1535, TA1537 and TA1538) were incubated with ethyl (-tolyloxy)acetate (No. 1027) at up to 3600 µg per plate (Wild et al., 1983), 2-phenoxyethyl isobutyrate (No. 1028) at 3600 µg per plate (Wild et al., 1983) or sodium 2-(4-methoxyphenoxy)propanoate (No. 1029) at up to 5000 µg per plate (Varley & Trenchard-Morgan, 1985), with or without metabolic activation.
Ethanol fermentation | Alcohol dehydrogenase | …
No significant difference in body-weight gain was found between test and control animals. The kidneys of male rats given phenethyl senecioate (No. 998) were slightly enlarged, but the slight increase in relative weight became less marked when the values were compared with those for control groups in the same laboratory. The authors concluded that the changes in kidney weight were not toxicologically significant. No effects were observed in either male or female rats given isopropylphenylacetaldehyde (No. 1024) or ethyl (-tolyloxy) acetate (No. 1027) (Posternak et al., 1969).
The Short-Chain Alcohol Dehydrogenase ABA2 Catalyzes …
In a study on rabbits, it was stated that aliphatic alcohols appeared to be metabolized and eliminated from the body by: (a) oxidation and elimination of the products (acids, aldehydes, ketones, and carbon dioxide) in the urine and expired air; (b) conjugation as glucuronide or sulfate and elimination of the products in the urine; and (c) elimination of the unchanged alcohol in the expired air or urine.
SDR enzymes usually catalyze alcohol-ketone/aldehyde.
In the 90-day study, groups of 20 male and 20 female CD rats received sodium 2-(4-methoxyphenoxy)propanoate in the diet at a concentration of 0, 5000, 10 000 or 20 000 ppm, corresponding to 0, 250, 500 or 1000 mg/kg bw per day. Body-weight gain was reduced in males (17%) and females (20%) at the highest dose, and males at 500 mg/kg bw per day showed a 7% reduction in body-weight gain. The authors did not consider these figures to be statistically significant. Haematological examination and blood chemistry revealed normal values. No treatment-related changes were found in urine cellularity, volume, specific gravity, pH or protein, bilirubin or ketone content or in blood glucose or sodium concentration, however, a reduction in urine potassium concentration was seen in males at the highest dose during weeks 6 and 13 and in females at 500 and 1000 mg/kg bw per day during week 13 of the treatment period. No microscopic changes were found that could be related to administration of the test substance (Hill & Wood, 1986).