Acetic anhydride

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
A similar systemic toxicology profile should apply to acetic anhydride and acetic acid since acetic anhydride is rapidly and completely transformed to acetic acid. In contrast at the point of initial contact, each substance should require a specific assessment of local effects.

Additional information

Although no toxicokinetic studies (human or non-human) are directly available for acetic anhydride it is known that this substance, like many acid anhydrides, readily hydrolyses within an aqueous environment to produce, in this case, acetic acid.

Rate calculations derived from first principles have considered the maximum rate of hydrolsis of acetic anhydride by water in air at both 20 and 40^oC with resulting half-life values of 6.5 and 2.8 minutes, respectively (personal communication with Pete Wilson, BP Chemicals, 1998).
The half-life of the hydrolysis has been measured for several acid anhydrides, at an initial concentration 2mM, in carbonate buffer at pH7.4 (Brown et al., 1978). For acetic anhydride these authors reported a half-life of about 3 minutes (182 seconds). The half-life of the hydrolysis is likely to reduce as the pH of the environment increases.

Within the context of mammalian toxicology therefore one might consider that even if some acetic anhydride were absorbed systemically as the intact molecule, it would quickly hydrolyse in vivo (pH=7.4) to acetic acid and therefore the systemic toxicity of acetic acid should be relevant to acetic anhydride. A consequence of these considerations is that, at a sufficiently high concentration, acetic anhydride will induce local effects at the site of initial contact, but any systemic effects are more likely to be mediated by the natural product, acetic acid. Therefore the disposition of acetic acid in vivo is critical to understanding the systemic toxicity of acetic anhydride.

Absorption of Acetic Acid

Acetic acid, itself, is absorbed from the gastrointestinal tract. Absorption of acetic acid from the pylorus-ligated stomach of rats over a 6 hour period showed a log-dose response; approximately 100% was absorbed at a dose of 20 mg/rat, this decreased to approximately 30% when the dose was increased to 420 mg/rat (Hertling et al., 1956). The proportion of ionised (acetate) relative to non-ionised (acetic acid) is pH dependent. When either acetic acid or sodium acetate is orally administered to rats, the pH within the environment of the stomach is low (about pH=2 in rat) and the absorbed material is likely to be the same (acetic acid) whether acetic acid or the sodium salt was administered. Following absorption from the gut to the blood, the pH of which is 7.4, the vast majority of the absorbed material will be then be present as acetate, irrespective of which form was administered.

Metabolism

Following the rapid hydrolysis of acetic anhydride, acetic acid is formed. In blood (pH=7.4) only 0.23% of the acid will be non-ionised and capable of crossing lipid barriers. The ionized form, acetate, has a central role in normal intermediary metabolism; it reacts with coenzyme A before entering the citric acid cycle as acetyl-coenzyme A (Acetyl-CoA). Acetyl-CoA is utilised in the mitochondrial citrate cycle or channeled into other endogenous processes such as fatty acid synthesis. The capacity of the cycle in man is approximately 640 mg acetate/kg/day (Simoneau et al., 1994).

Rats given radiolabelled acetate in diet excreted approximately 50% of the radiolabel as CO2 (Lunberg, 1988; cited by Health Council of the Netherlands, 2004). Humans given 120 mg acetate/kg bw in a drink converted about 80% to CO2 within 90 minutes (~ 0.5 mg acetate/kg bw removed per minute) (Smith et al., 2007).

Excretion

The elimination half life of acetate from the blood of dogs administered sodium acetate intravenously (3-6 mmol/kg) was 3-5 minutes (Freundt, 1973). In rabbits, acetate was rapidly eliminated from blood following intravenous administration (0.5-1 g sodium acetate/kg bodyweight), mean residence time (MRT) and dose normalised AUC increased with dose indicating saturable elimination kinetics. The elimination of acetate from blood was best described by a two compartment open model with Michaelis-Menten elimination kinetics (Fujimiya et al., 1999).

Citations

Brown NA et al. (1978) The relationship between acylating ability and teratogenicity of selected anhydrides and imides. Toxicol & Appl Pharmacol V45 p361

Health Council of the Netherlands (2004): Committee on Updating of Occupational Exposure Limits. Acetic acid; Health-based Reassessment of Administrative Occupational Exposure Limits. The Hague: Health Council of the Netherlands, 2000/15OSH/113.

Lundberg P (1988): Consensus report for acetic acid. In: Scientific basis for Swedish Occupational Standards IX. Arbete och Hälsa 32 pp132-7

Simoneau S et al (1994) Measurement of Whole Body Acetate Turnover in Healthy Subjects with Stable Isotopes. Biological Mass Spectrometry, V23, pp 430 -433