Esters of Mono‐, Di‐, and Tricarboxylic Acids

Abstract

This chapter presents information on esters of mono-, di-, and tricarboxylic acids with monoalcohols from 1 to over 10 carbons in either a straight chain or branched configuration. In general, the properties (chemical and functional) change with the carbon length of the alcohol. Properties shift from higher water solubility and lower boiling point to lower water solubility and higher boiling point for esters of a particular acid group. There is insufficient information to conclude that the carbon length of the acid group influences the properties significantly. Also included are esters of the trialcohol, glycerol, with monocarboxylic acids. These substances are included for the sake of completeness. All esters are subject to hydrolysis, especially enzymatic hydrolysis. Most esters in biotic systems hydrolyze primarily to the carboxylic acid and alcohol. There are some exceptions such as esters of phthalic acid that form relatively stable monoesters in biotic systems, which can be further oxidized. The uses of various esters are reviewed below and they vary with the acid. The simple aliphatic esters of benzoic acid are liquids that are used as solvents, flavors, or perfumes. Benzyl benzoate is used as a miticide or as a plasticizer. In general, these compounds have a low order of toxicity. The primary effects expected from the ingestion of moderate amounts of benzoates are gastrointestinal (GI) irritation, gastric pain, nausea, and vomiting. Available data indicate a low order of skin absorbability, and the undiluted materials may be either slight or moderate skin irritants. In rabbits, the degree of skin irritation caused by alkyl benzoates increases with an increase in molecular weight. The salicylates are used as flavorants, perfumes, or analgesics. The most commonly used member of this class of compounds is methyl salicylate. Ingestion of relatively small quantities of methyl salicylate may cause severe, rapid-onset salicylate poisoning. The lower alkyl esters of p- or 4-hydroxybenzoic acid (C1–C4), also named the methyl-, ethyl-, propyl-, and butyl parabens, are high-boiling liquids that decompose on heating. They are widely used in the food, cosmetic, and pharmaceutical industries as preservatives, bacteristats, and fungistats. Parabens also have been used therapeutically in the treatment of moniliasis, a Candida albicans infection. By the oral route, parabens are rapidly absorbed, metabolized, and excreted. The lower paraben homologues have low potential for acute or chronic systemic toxicity and are therefore approved as human food additives. Cinnamates (phenyl acrylates and phenylpropenoic acid esters) are mainly used as fragrances in the perfume industry. Cinnamates appear to have low to moderate toxicity in mammals. In humans, dermal exposure to allyl cinnamate may cause skin irritation. Some p-aminobenzoic acid (PABA) esters occur naturally, because the free compound, PABA, that is utilized for their synthesis, is an intricate part of the vitamin B complex. PABA esters exhibit a low order of acute toxicity in experimental animals. In humans, cases of methemoglobinemia after topical benzocaine or procaine use have been reported. Sunscreen agents containing PABA esters may occasionally produce allergic photosensitization. The o-aminobenzoates (anthranilates) are less irritating and less likely to cause sensitization than do the p-aminobenzoates, but have less therapeutic usefulness. They are used in some sunscreen lotions. Anthranilates have low toxicity potential. Long-chain fatty acids of glycerides may be replaced by one or more acetyl groups to produce mono-, di-, or triacetin. Acetins, propionates, and butyrates serve as food additives, solvents or plasticizers, and surface-active agents. Available evidence indicates that these agents exhibit a low order of toxicity. Normally, no irritant effects occur upon inhalation or direct dermal contact. The higher glycerides of fatty acids with odd-numbered carbon chains (C5–C11) are found naturally in very small quantities in diverse organisms, and the even-numbered (C12–C24) esters are common nutritional constituents. They are used as emulsifiers for foods, industrial raw materials, or nonacid detergent components. Some toxicity data are available for the C5 and C8 compounds. The even-numbered C12–C18 glycerides are nontoxic. Little toxicological information is available about resorcinol ester compounds. Gallates are chemically trihydroxybenzoic acid esters. They serve generally as antioxidants, and the propyl, octyl, and dodecyl gallates have been approved as food additives. The gallates exhibit low acute and chronic toxicity in experimental animals. The bulk of evidence suggests that they are not carcinogenic or teratogenic. Oxalates, malonates, glutarates, and succinates are high-flash, high-boiling fluids. Oxalates and malonates are mainly used as solvents for resins or as chemical intermediates. The general industrial use of these materials has not been associated with any particular toxicity problem. Diethyl oxalate, which can exert typical local solvent and systemic effects, may present an exception. In humans, diethyl oxalate may cause irritation to skin and mucous membranes. Chemical and physical data for alkyl and alkoxy adipates, azelates, and sebacates are summarized. These compounds are important chemical intermediates and are used extensively as plasticizers. Some of these agents are used in food packaging materials. They possess low acute toxicities, and their irritant effects on the skin and eyes are very slight. Available evidence suggests that the lower alkyl adipates (dimethyl, diethyl, and dibutyl) are reproductive and/or fetal toxicants. Maleic acid esters (cis-2-butenoates), fumarates (trans-2-butenoates), and itaconates have been utilized as plasticizers, raw materials for chemical syntheses, or preservatives for fats and oils. The esters of alkenyl dicarboxylic acids are of low acute toxicity. They have a tendency to cause skin or eye irritation in rabbits. Allergic dermatitis has occurred in humans exposed to dibutyl maleate. Chronic and subacute toxicity data for these compounds are limited. The aromatic o-dicarboxylic acid (phthalate) esters are among the most important industrial chemicals and perhaps the most studied esters of carboxylic acids. They are used as plasticizers for a variety of plastics; those of C8 and above are used to add flexibility to PVC. They are also used with vinyl and cellulose resins to lend toughness and flexibility. They are commonly used in wire and cable coverings, moldings, vinyl consumer products, and medical devices. Some low-molecular-weight phthalate esters (e.g., methyl, ethyl, and butyl) are used as industrial solvents rather than as plasticizers. Occasionally, these low-molecular-weight phthalates have applications for consumer products such as ink and lacquer. Physically, phthalates occur mainly in liquid form with high boiling ranges and very low vapor pressures, both of which contribute to the high stability of these materials. The biological responses to phthalate esters vary based on the alcohol side chain and the animal species tested. Generally, biological responses are greatest for butyl (C4) to hexyl (C6) alcohol esters, including branched hexyl alcohol esters. In general, all phthalate esters have low potential for acute toxicity following oral, dermal, or inhalation exposure. They are nonirritating or slightly irritating to the skin and eyes, and they are not sensitizers. Developmental and reproductive toxicity is most associated with the C4–C6 alcohol esters, and carcinogenesis in two species has been demonstrated for two esters. Rodents are most sensitive for these endpoints; primates appear to be insensitive. Keywords: acetins; adipates; aminobenzoates; azelates, benzoates; butylates; citrates; cinnamates; fumarates; glutarates; glycerol acetates; glycolates; hydroxybenzoates; itaconates; maleates; malonates; oxalates; parabens; phthalates; propionates; salicylates; sebacates; succinates; sulfosuccinates; trimellitates